Pertussis

Pertussis, referred to as whooping cough, is an upper respiratory infection caused by the bacterium, Bordetella pertussis (written in studies as B. pertussis). Pertussis presents as a deep and harsh cough that is worse at night and does not include fever. While the infection usually lasts 6 weeks, the severity can vary widely – from nothing more than a runny nose to a very severe, persistent barking cough. Pertussis tends to be more serious in children under six months of age due to the very small size of their trachea (wind pipe.) Whooping cough can affect people of any age. Anyone who has a persistent cough lasting more than 30 days should be suspected of having pertussis.

Pertussis vaccines have several forms and several manufacturers. Whole cell pertussis vaccines (DTwP) have been used since the 1940s and is still used in foreign countries. Since 2002, the U.S. has used exclusively acellular pertussis vaccines (DTaP). In 2005, a new pertussis vaccine was released for adolescents and adults (Dtap).

Acellular pertussis vaccines - "There is as yet no consensus about the antigenic composition of an ideal acellular pertussis vaccine. Acellular pertussis vaccines currently available from different manufacturers should be considered as different and unique products because of the presence of one or more different components…These individual antigens may be derived from different strains of Bordetella pertussis and have been purified by different methods. For these reasons the protective efficacy in humans of various manufacturers' products may be based on different mechanisms, which complicates the direct comparison of the protective activity of various products and new formulations by means of simple laboratory tests. Indeed, no '''unequivocal immunological correlates of protection against pertussis have yet been demonstrated, nor has a generally accepted animal model to predict clinical efficacy been validated. Comment: This is a very important paper and essentially admits that they have no idea how the pertussis vaccine works, and that the components are not known to "protect."

December 8, 2018 - Burden of Children Hospitalized With Pertussis in Canada in the Acellular Pertussis Vaccine Era, 1999–2015 (full text) “Prematurity and female sex were significantly associated with increased risk for death (5-fold and 3.5-fold increase, respectively).”

Potential conflicts of interest.

• M. S. is and has been an investigator on research grants received from Pfizer, Merck, and Variation Biotechnologies, Inc; all monies have been paid to his institution, and he has received no personal payments.
• S. A. H. has received grants and contracts for research from Sanofi Pasteur and GlaxoSmithKline, both producers of aP vaccine.

October 8, 2018 – Reactogenicity and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant and nonpregnant women “374 pregnant and 225 nonpregnant women were vaccinated. Severe local or systemic reactions or “any” fever were uncommon (≤3% for both groups). Moderate/severe injection-site pain was significantly higher in pregnant (17.9%) versus nonpregnant (11.1%) women, but did not prompt a healthcare visit. Proportions of other moderate/severe or any severe reactions were not significantly higher in pregnant compared to nonpregnant women. Moderate/severe (including pain) and severe reactions were not significantly higher in pregnant women receiving repeat versus first-time Tdap.”

Potential conflicts of interest

• KME was on a Data and Safety Monitoring Board for a Novartis funded influenza vaccine in children and received research funding for studies of Group B streptococcus vaccine in pregnant women produced by Novartis.
• GKS is on a Data and Safety Monitoring Board for a GlaxoSmithKline funded RSV vaccine study in pregnant women. She has received research funding for studies of Group B streptococcus vaccine in pregnant women produced by Novartis and for RSV vaccine in pregnant women produced by Novavax.
• KBF has received research funding for studies of Group B Streptococcus vaccine in pregnant women produced by Novartis and for RSV and CMV surveillance among pregnant women and their infants by Pfizer and Regeneron. 
• EBW has received funding from CSL, GlaxoSmithKline, Merck, Novartis, Novavax, and Pfizer to conduct clinical research studies. He has received support from Novartis as a member of a Data Safety Monitoring Board and from Merck as a consultant. The other authors report no conflict of interest.”

July 2018 -Safety Surveillance of Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) Vaccines (full text) "'Among all DTaP vaccine reports, 5627 (11.2%) were coded as serious, including '844 (1.7%) death reports. The most frequently reported PTs for all reports were injection site erythema (12 695; 25.3%), pyrexia (9913; 19.8%), injection site swelling (7542; 15.0%), erythema (5599; 11.2%), and injection site warmth (4793; 9.6%) (not shown in tables). Table 2 shows the 10 most common PTs reported for serious and nonserious reports. ... In total, 844 deaths were reported to VAERS after receipt of DTaP vaccines. Death certificates, autopsy reports, or medical records were obtained for 725 (85.9%) reports (Table 3). Among these 725 reports, the most frequent cause of death (350 of 725; 48.3%) was sudden infant death syndrome ('SIDS'). Most SIDS cases (217 of 350; 62.0%) occurred among male infants; the predominant age group was infants <6 months of age (318 of 350; 90.9%)."

May 3, 2018 -Coverage of recommended vaccines during pregnancy in Flanders, Belgium. Fairly good but can we do better? "In Flanders, more than two-third of pregnant women receives pertussis vaccination but less than half of them receives the influenza vaccine. Further improvement for both maternal vaccination programs can be achieved by targeting the underserved populations and diminishing'vaccination hurdles."

April 19, 2018 - A phase III, open-label, randomised multicentre study to evaluate the immunogenicity and safety of a booster dose of two different reduced antigen diphtheria-tetanus-acellular pertussis-polio vaccines, when co-administered with measles-mumps-rubella vaccine in 3 and 4-year-old healthy children in the UK"During the 31-day (Days 0–30) post vaccination unsolicited reporting period, 88/255 (34.5%; dTap-IPVB) and 36/130 (27.7%; dTap-IPVR) (p = 0.22) of participants reported at least one AE of which 4.7% and 4.6% (p = 1.0) respectively were considered to be severe. Diarrhoea and vomiting, reported for 9/255 (3.5%) participants were the most frequently reported unsolicited AE in the dTap-IPVB group while rash, reported for 6/130 (4.6%) participants was the most frequently reported unsolicited AE in the dTap-IPVR group. One SAE was reported during the whole clinical study duration; pneumonia requiring hospitalisation reported for one participant in the dTap-IPVB arm. This was felt not to be causally related to vaccination by the investigator. No study participants withdrew from the study due to an AE or SAE.

February 8, 2018 - Randomized Controlled Trial of the Safety and Immunogenicity of Revaccination With Tetanus-Diphtheria-Acellular Pertussis Vaccine (Tdap) in Adults 10 Years After a Previous Dose (full text) "A total of 8 (0.8%) participants in the Tdap group and 1 (0.3%) participant in the Td group reported an SAE; none were considered vaccine related. A 23-year-old woman became pregnant approximately 12 days after her Tdap vaccination and experienced a spontaneous abortion 38 days after vaccination. The SAEs post tonsillectomy bleeding, mononucleosis and tonsillitis, breast neoplasm, abdominal pain, Crohn's disease, Pickwickian syndrome, and partial bowel obstruction (Tdap group) and a fractured arm (Td group) occurred 25 to 149 days after vaccination. ... Although data exist to support the safety and tolerability of tetanus-, diphtheria-, and pertussis-containing vaccines administered at an interval as short as 1 month, data from direct evaluations of Tdap revaccination at intervals less than 4 to 5 years are not yet available. The results of this study provide additional data to support the use of booster doses of Tdap to maintain protection against pertussis in adults." Financial support. This study was funded by Sanofi Pasteur.

January 2018 - A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial "28 days after vaccination, seroconversion rates in the aP(PTgen/FHA) group were 96·0% (95% CI 92·8–99·1; n=142) for anti-pertussis toxin IgG and 93·2% (89·2–97·3; n=138) for anti-filamentous haemagglutinin IgG. These findings support the non-inferior immunogenicity of TdaP(PTgen/FHA) over comparator Tdap. Reactogenicity and incidence of adverse events were similar between groups. ... "Results of our trial led to the licensure of new acellular pertussis vaccines containing genetically inactivated pertussis toxin in Thailand. The availability of recombinant monovalent pertussis vaccines that induce high antibody responses provides the medical community and consumers with the opportunity to vaccinate against pertussis when immunisation against diphtheria and tetanus is not required or not desired. 'Studies are underway to pave the way for licensure studies of this acellular pertussis vaccine in other countries."

October 6, 2017 - Pertussis-associated persistent cough in previously vaccinated children "This study used non-invasive testing to show that pertussis is one of the most important causes of long-lasting cough in school-age subjects. Moreover, the protection offered by acellular pertussis vaccines currently wanes more rapidly than previously thought."

August 1, 2017 - Risk Markers for Pertussis Among Infants <4 Months of Age: Understanding the Hispanic Disparity. "Methods: We evaluated infants born in California during 2013-2014; cases were infants reported to CDPH with pertussis occurring before 4 months of age and controls were infants who survived to at least 4 months of age without pertussis. Bivariate comparisons and multivariate logistic regression models were used to identify risk markers for pertussis in Hispanic and non-Hispanic infants. ... Conclusions: Infants of all races/ethnicities with older siblings or born to younger mothers are at increased risk of pertussis. Among Hispanic infants, prematurity and Medicaid insurance were independent risk markers for pertussis. These factors highlight the need to ensure prompt immunization of pregnant women with Tdap at the earliest opportunity starting at 27 weeks gestation. Comment: Mothers who are not breatfeeding risk providing protection from infections and viruses.

July 20, 2017 - A National Seroepidemiologic Survey of Pertussis among School Children in Taiwan. "Conclusion: The prevalence of anti-B. pertussis antibody was 42.5% in Grade 1-9 students under the current vaccination program in Taiwan. Antibody induced by the booster vaccination before entry of primary school waned rapidly in 3-4 years. Rapid waning of anti-B. pertussis antibody may explain the resurgence of whooping cough in recent decades. Additional booster doses should be considered in adolescents and adults."

July 1, 2017 - Live Attenuated Pertussis Vaccine BPZE1 Protects Baboons Against Bordetella pertussis Disease and Infection "This comparison showed that a single BPZE1 administration with 1010 CFU outperformed 3 full human doses of acellular pertussis vaccine by 99.8% against total nasopharyngeal bacterial burden using matching protocols. ... Given mounting evidence that nasopharyngeal colonization with B. pertussis is common, that transmission of B. pertussis by nasopharyngeally colonized individuals plays an important role in the rising incidence of pertussis in recent decades, and that current pertussis vaccines fail to prevent nasopharyngeal B. pertussis colonization, the results of this study provide important evidence of a promising path forward." Comment: Please see the FDA animal rule here "FDA will rely on animal efficacy data for approval of vaccines using the Animal Rule only when the animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or the prevention of major morbidity. To estimate efficacy of vaccines in humans using the Animal Rule, the vaccine dose chosen for adequate and well-controlled animal efficacy studies should elicit an immune response in animals reflective of that in human's. Using pilot and proof-of-concept studies, a relationship should be established between the vaccine dose and the desired immune response, depending upon the study endpoint."

June 15, 2017 - Effect of Prepregnancy Pertussis Vaccination in Young Infants "Prepregnancy Tdap vaccination significantly increases maternal antibody concentrations in consecutive infants. However, similar to the effect of Tdap vaccination during pregnancy, immune responses of later-born infants born to mothers who received a prepregnancy immunization, are blunted. Comment: The future of pertussis vaccine may resemble that of the influenza vaccine' - a shot every year.

June 8, 2017 - Waning protection following 5 doses of a 3-component diphtheria, tetanus, and acellular pertussis vaccine (full text) "This study found that among children who had only ever received DTaP3 vaccines, pertussis risk increased, on average, by 27% each year as vaccinees got farther away from their 5th dose of DTaP3. Similarly, when evaluating waning after 5 DTaP doses regardless of manufacturer, pertussis risk increased by 30% for each additional year after the receipt of the 5th DTaP dose."

• Conflicts of interest NPK and RB received research grant from the GSK group of companies for the study conduct.
• NPK and RB report unrelated research support to their institution from the GSK group of companies, Sanofi Pasteur, Merck and Co, Pfizer, MedImmune, Nuron Biotech, and Protein Science. POB is employed by the GSK group of companies and holds shares in the GSK group of companies as part of his employee remuneration.
• GK was employed by the GSK group of companies at the time of the study conduct and is currently employed by CSL Behring. GK also reports holding of shares in the GSK group of companies and in CSL Behring as part of her employee remuneration.
• Funding GlaxoSmithKline Biologicals SA funded this study (NCT02447978) and was involved in all aspects of the study, including study design and interpretation of the data. GlaxoSmithKline Biologicals SA took charge of any publication costs.

March 14, 2017 - Pertussis Antibody Transfer to Preterm Neonates After Second- Versus Third-Trimester Maternal Immunization (full text) "Information on prior Tdap vaccination is limited to the last 5 years, and may not exclude occult exposure to pertussis. Second, it does not include data for preterm neonates born before GW 30 0/7 and lacks power to detect an effect for preterm births between GW 30 0/7 and 33 6/7. Further studies are warranted to assess the benefits from early maternal immunization for very early preterm neonates."

• Potential conflicts of interest. C.-A. S. has received grant support for preclinical and clinical studies from several vaccine manufacturers and has been part of the scientific advisory board of BioNet-Asia since March 2016.
• J. P. is the co-founder and chief scientific officer of BioNet-Asia and has filed a patent for a recombinant Bordetella pertussis strain. All other authors report no potential conflicts.

February 22, 2017 - Reporter cell lines for detection of pertussis toxin in acellular pertussis vaccines as a functional animal-free alternative to the in vivo histamine sensitization test (full text) PTd is thought to be key for vaccine-induced protective immunity [1] and, while pertussis toxin (PTx) together with LPS are considered responsible for the occasional side effects after wP vaccination and PTx for side effect of aP vaccination. For aP vaccines, regulatory authorities require monitoring for inactivation of PTx and reversion to toxicity through the murine histamine sensitization test (HIST). The HIST is based on the principle that PTx reduces the lethal dose of histamine 30–300 fold . However, since the test lacks mechanistic understanding, suffers from standardization problems and causes severe animal suffering, there is an urgent need for an alternative test method.

February 2017 - A Phase III Randomized, Double-blind, Clinical Trial of an Investigational Hexavalent Vaccine Given at Two, Three, Four and Twelve Months (full text) "A hexavalent vaccine [diphtheria–tetanus toxoids–pertussis, hepatitis B vaccine, inactivated poliovirus vaccine and H. influenzae type b (DTPa3–HBV–IPV/Hib); Infanrix-hexa (GlaxoSmithKline Inc., Mississauga, Ontario, Canada); Control] has been licensed in Europe for over a decade (the only hexavalent vaccine available at the time of the study), a period during which improvement in immunization timeliness and stable effectiveness in disease prevention has been observed." . . . "The fully liquid investigational hexavalent vaccine [diphtheria–tetanus toxoids–acellular pertussis 5, hepatitis B, inactivated poliovirus vaccine and H. influenzae type b (DTaP5–HB–IPV–Hib)] reported here contains a 5-antigen pertussis component and has a different carrier protein conjugated to the Hib antigen. This report presents results from a pivotal European Union Phase III study (NCT01341639), assessing the safety, tolerability and immunogenicity of DTaP5–HB–IPV–Hib compared with Control, when administered at 2, 3, 4 and 12 months, concomitantly with Prevenar 13 (PCV13) (Pfizer, Philadelphia, PA), RotaTeq (RV5) (Merck & Co., Inc., Kenilworth, NJ) and ProQuad (MMRV) (Merck & Co., Inc., Kenilworth, NJ). Another study of DTaP5–HB–IPV–Hib and Control when administered in the 2-month, 4-month, and 11-month to 12-month schedule has also been completed and is described in a separate manuscript.

• Funding for this research was provided by Merck & Co., Inc., Sanofi Pasteur, Inc. and Sanofi Pasteur MSD. Although the funding companies formally reviewed a penultimate draft, the opinions expressed are those of the authors and may not necessarily reflect those of the sponsors. All coauthors approved the final version of the manuscript.
• T.V., T.B., A.F.V. and K.P. were investigators for the sponsor supported by research grants.
• M.F.P., S.A.F., J.X., G.F.L., J.E.S. and A.W.L. are employees of Merck & Co., Inc. and may hold company stock and/or stock options.
• F.B., S.T. and E.Z. are employees of Sanofi Pasteur MSD.

January 3, 2017 - Age-specific effectiveness following each dose of acellular pertussis vaccine among infants and children in New Zealand "To consider whether genetic adaptation of the pertussis organism may be affecting the longevity of VE from acellular vaccines, future studies should incorporate characterisation of pertussis strains. This study supports the NZ immunisation strategy of a primary course starting at age 6 weeks and a booster dose in the fourth year of life."

• Conflict of interest Conectus at the University of Auckland has received various unrestricted grants from GlaxoSmithKline Biologicals, manufacturer of Boostrix®.
• H.P-H. has served on advisory panels for GlaxoSmithKline, Merck Sharp and Dohme, and Pfizer, but has not personally received honoraria. .

January 3, 2017 - Estimating Pertussis Susceptibility Among 0-23-Month-Old Children in the United States. Using National Immunization Survey (NIS) 2013. "In sensitivity analysis, increasing maternal pertussis vaccination coverage from 10% to 42%, decreased susceptibility in children less than 2 months of age to 68%. When considering waning immunity following the fourth dose of vaccine, the herd protection threshold was no longer reached. Conclusions: These estimates underscore the need to monitor age-specific pertussis vaccine coverage, to increase childhood and maternal pertussis vaccine coverage, to maintain population level immunity and to prevent the spread of pertussis among young children."

December 23, 2016 - Genome-Wide Association Mapping of the Antibody Response to Diphtheria-Tetanus-acellular Pertussis Vaccine in Mice "This study provides novel insights into the genetic basis and potential candidate genes for differences in the IgG responses to vaccination."

December 20, 2016 - Vaccine hesitancy and healthcare providers (full text) "Although the data indicates that self-vaccination among HCPs is clearly related to their willingness to recommend vaccination to others, some HCPs expressed a clear view that their own vaccination behaviour is their own choice, as is the choice of their patient. In a study conducted in Israel, nurses reported that they did not see the importance of being role models regarding pertussis vaccination and instead felt their autonomy' to decide whether or not to be vaccinated was of greater concern."..."Parents had significantly higher odds of accepting a vaccine if the provider initiated a consultation using a presumptive approach (e.g., “Today we’re going to be vaccinating your child with …”) which projected more confidence about vaccination than when they opened the conversation with a statement that was aiming to be engaging (e.g., “how do you feel about vaccination?”), but suggested that the provider was uncertain."

December 12, 2016 - Lack of Pertussis Protective Antibodies in Healthcare Providers Taking Care of Neonates and Infants in a Children's Hospital. "Contact tracing and seroepidemiologic studies were done after a premature baby contracted pertussis in a children's hospital. No infection source was confirmed. Four (3.5%) healthcare providers were positive for anti-pertussis IgM, while only 23 % (26/113) positive for IgG in a following survey. Pertussis vaccination for healthcare providers is needed."

November 21, 2016 - Pertussis: Biology, epidemiology and prevention "Despite long-standing vaccination programs, substantial increases in reported cases of pertussis have been described in several countries during the last 5 years."..."Multiple hypotheses including but not limited to the availability of more sensitive diagnostic tests, greater awareness, and waning vaccine-induced immunity over time have been posited for the current challenges with pertussis."

October 17, 2016 - Survey of Household Contacts of Infants with Laboratory Confirmed Pertussis Infection During a National Pertussis Outbreak In England and Wales. "Results: In total 220 contacts from 63 families were included in the analysis. In 86% of households (54/63) at least one positive result was found with 44% (97/220) of all contacts testing positive. Around 29% (31/108) of non-coughers tested positive. A probable source of infection was found for 46% (29/63) of infant cases. Mothers were the probable source in 38% of cases, followed by siblings (31%) and fathers (10%)." Comment: The UK is now pushing for the TDaP 'in pregnancy we will see more fetal deaths, and more $ for big pharma.

November 2016 - Two Distinct Episodes Of Whooping Cough Caused By Consecutive Bordetella Pertussis And Bordetella Parapertussis Infections In A Fully Immunized Healthy Boy "'WHO-sponsored studies had used incorrect methodology and introduced survival bias into the analysis.15–17 In these studies, the date of DTP vaccination had been updated retrospectively at the next household visit. If the child died before the next household visit, updating of vaccination status did not happen because the family had usually discarded the vaccination card of a dead child (Fig. 1, scenario 1). Hence, children who died, but had been vaccinated, would be misclassified as “unvaccinated” for lack of other information. In other words, these procedures allocate risk-free survival time to the vaccinated group and misclassify some dead vaccinated children as unvaccinated."

October 11, 2016 - Antimicrobial Susceptibility and Molecular Detection of Pertactin-Producing and Pertactin-Deficient Bordetella Pertussis. "Resurgence of B. pertussis in recent years in the US has coincided with a dramatic rise in pertactin-deficient strains." Comment: Not unvaccinated children.

October 11, 2016 - Antimicrobial Susceptibility and Molecular Detection of Pertactin-Producing and Pertactin-Deficient Bordetella Pertussis. "Resurgence of B. pertussis in recent years in the US has coincided with a dramatic rise in pertactin-deficient strains." Comment: Not unvaccinated children.

October 2016 - SIDS and Other Sleep-Related Infant Deaths: Evidence Base for 2016 Updated Recommendations for a Safe Infant Sleeping Environment "Four of the 6 studies showed no relationship between diphtheria-tetanus toxoids-pertussis vaccination and subsequent SIDS; the other 2 suggested a temporal relationship, but only in specific subgroup analysis." Comment: It is this specific subgroup that needs to be exempt from vaccinations, until this subgroup is established, there should be liability for pharmaceutical manufacturers.

September-October 2016 - Complete Genome Sequences of Bordetella pertussis Vaccine Reference Strains 134 and 10536 "However, many countries have recently experienced disease resurgence, in part due to genetic divergence of circulating strains. The resulting antigenic mismatch with vaccine references has led many to conclude that B. pertussis is evolving under vaccine-driven selection.

August 2016 - Evolution of Bordetella pertussis "After the introduction of vaccination, mainly ptxP1 alleles were detected. The vaccine strains also harbor ptxP1. Although isolates with ptxP3 were first detected in the late 1980's their rapid expansion in many industrial countries started in the last 1990's at a tune when ACVs were being introduced. Today, the ptxP3 isolates are common in Europe, Australia and the United States."

July 29, 2016 - The predicted persistence and kinetics of antibody decline 9 years after pre-school booster vaccination in UK children "Antibody responses to pertussis toxoid were undetectable in 49% of children at the 5 year follow up visit, and responses were predicted to be undetectable in 69% (95% CI 45–88%) of children by the time of their teenage booster at 13–14 years of age."..."Adding pertussis to the teenage booster for UK children as is done in other countries, would enhance immunity in adolescence."

July 6, 2016 - Two Distinct Episodes of Whooping Cough Caused by Consecutive Bordetella pertussis and Bordetella parapertussis Infections in a Fully Immunized Healthy Boy. "We describe a 5-year-old, fully immunized boy with PCR proven consecutive B. pertussis and B. parapertussis infections causing typical whooping cough at the age of 2 and 5 years, respectively. Neither pertussis immunization nor disease provides reliable immunity against further episodes of whooping cough."

June 30, 2016 - Pertussis vaccination during pregnancy in Belgium: Follow-up of infants until 1 month after the fourth infant pertussis vaccination at 15 months of age "All infants were vaccinated with Infanrix Hexa® according to the standard Belgian vaccination schedule (8/12/16 weeks, 15 months). We report results from blood samples collected before and 1 month after the fourth vaccine dose. Immunoglobulin G (IgG) antibodies against pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn), tetanus toxoid (TT) and diphtheria toxoid (DT) were measured using commercially available ELISA tests. Antibody levels were expressed in International Units per milliliter. Demographic characteristics were similar in the vaccine and control group. Before the fourth vaccine dose, significantly lower antibody titers were measured in the vaccine group compared to the control group for anti-Prn IgG (p = 0.003) and anti-DT IgG (p = 0.023), with a steep decay of antibody titers since post-primary vaccination. One month after the fourth dose, antibody titers were only significantly lower in the vaccine group for anti-PT IgG (p = 0.006). For all antigens, there was a rise in antibody titer after the fourth vaccine dose.

June 14, 2016 - Characterization of the immune response induced by pertussis OMVs-based vaccine "We have recently identified a vaccine candidate based on outer membrane vesicles (OMVs) derived from the disease etiologic agent that have been shown to be safe and protective in mice model of infection'."..."positioning this candidate among the different possibilities to constitute the third generation of anti-pertussis vaccines."

June 10, 2016 - Polymorphism of IL-10 gene promoter region: association with T cell proliferative responses after acellular pertussis vaccination in adults "Individual variation in immune responses is always encountered after vaccination. This phenomenon is also seen after acellular pertussis vaccination."..."One month after the vaccination, subjects with the AA and AG genotypes had a significantly higher T cell proliferative response against PT and FHA compared to those with the GG genotype. Subjects with the GG genotype had the lowest responses."

June 2016 - Continued pertussis outbreaks call vaccine effectiveness into question "Several studies have assessed the effectiveness of pertussis control with use of DTaP vaccines and DTwP vaccines. Klein and colleagues used a case-control design to evaluate pertussis control in children receiving primary pertussis vaccination from whole-cell and acellular vaccines. Patients aged 10 to 17 years in northern California diagnosed with pertussis via PCR testing (n = 138) were compared with PCR-negative (n = 899) and matched controls (n = 54,339). Risk for pertussis by the type of vaccine administered (acellular, whole-cell, or mixed use) was evaluated. Patients who received only whole-cell vaccines were more than fivefold less likely to be diagnosed with pertussis than subjects receiving only acellular vaccines or more than threefold less likely than patients receiving mixed whole-cell and acellular vaccines. The decreasing number of whole-cell pertussis vaccine doses was significantly associated with increased pertussis risk.' Comment: Are they promoting the return of the whole cell pertussis vaccine?

June 2016 - Bordetella pertussis: new concepts in pathogenesis and treatment "Recently emerging B. pertussis strains show evidence of genetic selection for 'vaccine escape mutants, with changes in vaccine antigen-expressing genes, some of which may have increased the virulence of this pathogen."

May 2016 - Vaccine Timeliness: A Cost Analysis of the Potential Implications of Delayed Pertussis Vaccination in the US - "Current DTaP vaccination was estimated to be delayed by 16, 27 and 44 days, for the first, second and third doses, respectively, relative to vaccination at exactly 60, 120 and 180 days. The model estimated that vaccination at exactly age 60, 120 and 180 days could prevent approximately 278 pertussis cases, 103 hospitalizations and 1 death in infants aged <1 year in the US, gaining approximately 38 quality-adjusted life years and saving approximately $1.03 million in healthcare costs." Comment: How many deaths would be reported in clinical trials where "not related to the vaccine" is used?

April 19, 2016 - Effect of different detoxification procedures on the residual pertussis toxin activities in vaccines "Due to multilevel reaction mechanisms of chemical detoxification that act on different molecular sites and with different production processes, it is difficult to define a molecular characteristic of a pertussis toxoid."..."Different types of vaccines, detoxified by formaldehyde, glutaraldehyde or by both, have different residual functional and individual baseline activities. Of the vaccines tested, PT toxoid detoxified by formaldehyde had the lowest residual PTx ADP-ribosyltransferase activity."

March 28, 2016 - The Pertussis Problem and a Possible Solution Will Parents Go Along? "What can we do to protect older children and adults from pertussis while we wait for new vaccines? The model reported by DeAngelis et al, also in this issue of JAMA Pediatrics might suggest an interim approach. This model evaluates what would happen if we brought back whole-cell pertussis vaccines. The authors suggest that we could achieve a dramatic reduction in pertussis cases by just giving an initial priming does of whole-cell vaccine in infancy, followed by the remainder of the vaccine series with acellular vaccine."..."But, can we really bring back whole-cell pertussis vaccine? Will parents accept a vaccine with more adverse effects? The reason acellular pertussis vaccines were developed in the first place was because whole-cell vaccine was felt by many to have unacceptably high rate of adverse effects." Comment: If it has been known for quite some time about the failure of the acellular vaccine, why did they push Tdap on adolescents and adults? There were many deaths caused by the whole-cell pertussis vaccine. Specific lots of vaccines caused deaths and debilitating adverse events. SeePertussis, DTaP/DTP, and VAERS.

March 28, 2016 - Epidemiological and Economic Effects of Priming With the Whole-Cell Bordetella pertussis Vaccine "Switching to a wP-priming vaccination strategy could reduce whooping cough incidence by up to 95% (95% CI, 91-98), including 96% (95% CI, 92-98) fewer infections in neonates. Although there may be an increase in the number of vaccine adverse effects, we nonetheless estimate a 95% reduction in quality-adjusted life-years lost with a switch to the combined strategy and a cost reduction of 94% (95% CI, 91-97), saving more than $142 million annually. Conclusions and Relevance Our results suggest that an alternative vaccination schedule including 1 dose of wP vaccine may be highly cost-effective and ethically preferred until next-generation pertussis vaccines become available.

March 28, 2016 - Impact of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccinations on Reported Pertussis Cases Among Those 11 to 18 Years of Age in an Era of Waning Pertussis Immunity " Between 1990 and 2014, 356 557 pertussis cases were reported in the United States. Of those, 191 914 (53.8%) were female and 240 665 (67.5%) were white. Overall incidence increased from 1.7 in 100 000 to 4.0 in 100 000 between 1990 and 2003, while latter years were dominated by epidemic peaks. Incidence was highest among infants younger than 1 year throughout the analysis period. Pertussis rates were comparable among all other age groups until the late 2000s, when an increased burden of pertussis emerged among children 1 to 10 years old, resulting in the second highest age-specific incidence. By 2014, 11- to 18-year-old individuals once again had the second highest incidence. While slope coefficients from segmented regression analysis showed 'a positive impact of Tdap immediately following introduction (slope, −0.4959; P < .001), a reversal in trends was observed in 2010 when rates of disease among 11- to 18-year-old individuals increased at a faster rate than all other age groups combined (slope, 0.5727; P < .001)."

March 2016 - Waning Tdap Effectiveness in Adolescents "On the basis of 1207 pertussis cases, Tdap VE during the first year after vaccination was 68.8% (95% confidence interval [CI] 59.7% to 75.9%), decreasing to 8.9% (95% CI –30.6% to 36.4%) by ≥4 years after vaccination."... "Conclustions: Routine Tdap did not prevent pertussis outbreaks. Among adolescents who have only received DTaP vaccines in childhood, Tdap provided moderate protection against pertussis during the first year and then waned rapidly so that litle protection remained 2-3 years after vaccination." Comment: Three unvaccinated children "did not have pertussis." The pertussis vaccine is a FAILURE. There are many articles that state the vaccine is not working: see Pertussis.

February 17, 2016 - Reciprocal interference of maternal and infant immunization in protection against pertussis "It may be important to determine the functionality of antibodies to evaluate potential interference of maternal and infant vaccination in protection against pertussis. Comment: This vaccine is off label for pregnant women. See Pregnancy

February 9, 2016 - Seroprevalence of pertussis amongst healthcare professionals in Spain "Overall, 31.2% of subjects were seropositive; 3.3% of these healthcare professionals had ELISA values indicative of current or recent infection. There were no significant differences in terms of pertussis prevalence with respect to age, gender, hospital department, profession, number of working years and number of hours spent with patients. These levels of seronegativity amongst healthcare workers further strengthen the rationale for vaccination amongst this specific population against pertussis."

February 7, 2016 - Protective Effect of Contemporary Pertussis Vaccines: A Systematic Review and Meta-analysis "Acellular (aP) and whole-cell (wP) pertussis vaccines are presumed to have similar short-term (<3 years after completion of the primary series) efficacy. However, vaccine effect varies between individual pertussis vaccine formulations, and many originally studied formulations are now unavailable. An updated analysis of the short-term protective effect of pertussis vaccines limited to formulations currently on the market in developed countries is needed."

February 3, 2016 - A behavioral economics intervention to increase pertussis vaccination among infant caregivers: A randomized feasibility trial "Only 1 subject redeemed the retail pharmacy Tdap voucher. Follow-up interviews suggest that, even with the voucher, significant barriers to vaccination remained including: delaying planned vaccination, perceived inconvenient pharmacy locations, and beliefs about pertussis risk and severity. Conclusions Despite leveraging existing infrastructure for adult vaccination, results suggest that retail pharmacy vouchers delivered during a newborn visit are not an effective strategy for promoting Tdap. Alternate approaches are needed that prioritize convenience and provide an immediate opportunity to vaccinate when motivation is high."

February 2016 - Bordetella pertussis Strain Lacking Pertactin and Pertussis Toxin "During the past 5 years, US B. pertussis isolates have become nearly 100% Prn-deficient (2,3) (unpub. data), and Prn-deficient' isolates have been obtained from vaccinated persons. The loss of Pt may represent a higher fitness cost to B. pertussis than the loss of Prn. In addition, the possibility that only the Pt-deficient isolates were recovered from patients 'who were co-infected with wild-type and mutant B. pertussis' cannot be discarded. Further testing in models to understand the clinical relevance of Prn- and Pt-deficient strains in vaccinated and unvaccinated persons is warranted. Although incidence of combined Pt- and Prn-deficiency in B. pertussis is rare, any increased mutation' in these or other acellular vaccine immunogens may have 'serious implications for the efficacy of current vaccines."

January 15, 2016 - Sustained Transmission of Pertussis in Vaccinated, 1–5-Year-Old Children in a Preschool, Florida, USA CME (full text) "Only 5 of 117 children in the preschool had not received the complete series of vaccinations. Of these 5 children, 2 were case-patients and both had received ≥1 dose of pertussis vaccine: the hospitalized 1-year-old child who had received a single dose and a 3-year-old child who had received only 2 doses. The other 3 children were 'unvaccinated but did not have pertussis."..."Short-duration vaccine effectiveness estimates for children receiving ≥3 doses of acellular pertussis vaccines have been described at ≥80%.[4,7,8] Although the small number of nonvaccinated children in the preschool resulted in a vaccine effectiveness that had extremely wide CIs that overlap 0, the low estimate, coupled with documented sustained transmission over a period of months, raises concerns about inadequate protection against pertussis in an age group believed to be well protected by acellular pertussis vaccination." Comment: Three unvaccinated children "did not have pertussis." The pertussis vaccine is a FAILURE.

January 12, 2016 - Pertussis specific cell-mediated immune responses ten years after acellular pertussis booster vaccination in young adults "After PT stimulation, only one (7.1%) subject had increased production in all cytokines, whereas six (42.9%) had decreased production of all cytokines. Ten subjects (71.4%) had decreased concentration of IFN-γ, the cytokine important for pertussis protection."

January 2016 - Trends in Pertussis Diagnostic Testing in the United States, 1990 to 2012 "Background: Reports of pertussis have been increasing in the US since the 1990s, and pertussis diagnostics have evolved during that time. Here, we describe temporal changes in pertussis diagnostic practices in the US during 1990 to 2012 and discuss potential implications."

Volume 15, Issue 1, 2016 - Predicting future trends in the burden of pertussis in the 21st century: implications for infant pertussis and the success of maternal immunization "To date,most mothers were primed in childhood with whole-cell pertussis vaccines. Soon, the generation of aP-primed individuals will become the new mothers-to-be. Theshorter duration of protection afforded by aP vaccines,which is more pronounced 'with repeated aP boosters', may lead to 'increased pertussis circulation among aP-primed parents. Maternal Tdap immunization in aP-primed mothers-to-be may become less effective. Additional measures to protect young infants may eventually be needed, along with new vaccines that induce higher quality and more durable responses."

2016 - Transferability study of CHO cell clustering assays for monitoring of pertussis toxin activity in acellular pertussis vaccines "Current regulations for acellular pertussis (aP) vaccines require that they are tested for the presence of residual or reversion-derived pertussis toxin (PTx) activity using the mouse histamine sensitisation test (HIST). Although a CHO cell clustering assay can be used by manufacturers to verify if sufficient inactivation of the substance has occurred in-process, this assay cannot be used at present for the final product due to the presence of aluminium adjuvants which interfere with mammalian cell cultures."

2016 - Alternatives to HIST for acellular pertussis vaccines: progress and challenges in replacement "Differences among aP vaccines include the number and quantity of antigen components per dose, the bacterial strain used for primary antigen production, methods of purification and detoxification, incorporated adjuvants, and the use of preservatives. The exact contribution of the different aP antigens to protection is not clear, but all vaccines currently on the market contain PTxd [chemically-inactivated pertussis toxin.] Regulators worldwide require manufacturers to test each aP vaccine lot to ensure both sufficient chemical inactivation of pertussis toxin (PTx) in the manufacture of PTxd and that PTxd has not reverted back to the active agent.

December 18, 2015 - The potential role of subclinical Bordetella Pertussis colonization in the etiology of multiple sclerosis "American schoolteachers and healthcare workers are at increased risk for symptomatic and asymptomatic BP infection. Government data indicate increased MS mortality among elementary and secondary school teachers, compared with all other professional occupations (proportional MS mortality: 161%, p < 0.0001), which persists after adjustment for gender, race and age. Increased MS risk among health technicians and nurses’ aides has also been demonstrated. Finally, the 2:1 female:male incidence ratio of MS mirrors the 2:1 female:male ratio of adult pertussis."..."The importance of BPTOX in MS modeling is highlighted by the fact that when neural antigens are introduced without BPTOX or other adjuvant, EAE is prevented, but when co-administered with BPTOX, EAE is induced."
Conflict of interest

• KR and SG are employed by ILiAD Biotechnologies, which is developing a vaccine for the prevention of Bordetella pertussis. KR has received salary and equity in ILiAD Biotechnologies and holds pending patents for an irrigation assembly. SG has an equity interest in ILiAD Biotechnologies.

Acknowledgment

• This work was funded by ILiAD Biotechnologies.

November/December 2015 - Complete Genome Sequences of 11 Bordetella pertussis Strains Representing the Pandemic ptxP3 Lineage "Pathogen adaptation has contributed to the resurgence of pertussis."..."Our analyses included six strains which do not produce the vaccine components pertactin and/or filamentous hemagglutinin."

November 17, 2015 - Pertactin negative Bordetella pertussis demonstrates higher fitness under vaccine selection pressure in a mixed infection model "Whooping cough or pertussis is a highly infectious respiratory disease in humans caused by Bordetella pertussis. The use of acellular vaccines (ACV) has been associated with the recent resurgence of pertussis in developed countries including Australia despite high vaccination coverage where B. pertussis strains that do not express pertactin (Prn), a key antigenic component of the ACV, have emerged and become prevalent."

September 2015 - Tracking Pertussis and Evaluating Control Measures through Enhanced Pertussis Surveillance, Emerging Infections Program, United States (full text) "Recently, the epidemiology of pertussis has indicated an increasing burden of disease among school-age children and adolescents, 'most of whom are up-to-date on pertussis vaccinations. Changes have also been identified in Bordetella pertussis at the molecular level, such as 'loss of pertactin, a key aP vaccine antigen.

August 28, 2015 - Influenza and Pertussis Vaccination among Pregnant Women and their Infants' Close Contacts: Reported Practices and Attitudes. " The response rate was 45%; 61% of mothers reported they and at least one close contact of their newborn had received influenza vaccine, and 67% reported this for Tdap. Infants whose mothers received influenza vaccine had a mean of 2.8 close contacts who also received influenza vaccine versus 0.9 contacts for mothers who did not receive influenza vaccine (p<0.0001). Infants whose mothers received Tdap had on average 2.4 contacts who also received it versus 0.8 for mothers who did not receive Tdap (p<0.0001). Factors associated with influenza and Tdap cocooning included obstetrician recommendation, high perceived benefits, low perceived barriers, and perceived susceptibility to disease. For Tdap, race/ethnicity was associated with cocooning (Hispanic/Latino, adjusted odds ratio 0.26, 95% confidence interval 0.10-0.64 referent to White)."

August 7, 2015 - Humoral and cell mediated immune responses to a pertussis containing vaccine in pregnant and nonpregnant women "One year after vaccination, cellular responses equaled the baseline levels detected prior to vaccination in both groups. In conclusion, a Tdap vaccination can increase vaccine specific IgG antibodies to the same extent in pregnant and in nonpregnant women, whereas the stimulation of vaccine specific Th1 type cellular immune responses with this 'acellular vaccine is transient and impaired during pregnancy."

August 2015 - Pertussis vaccines and the challenge of inducing durable immunity "Antibody levels wane rapidly following vaccination, likely a result of the inability of acellular pertussis antigens to stimulate long-lasting B cell memory. In addition, T cell responses to acellular pertussis vaccines are mixed Th2/Th1, while whole-cell pertussis vaccination and infection stimulate Th17 responses, important for host defense against extracellular mucosal pathogens."

July 9, 2015 - Needle-free and adjuvant-free epicutaneous boosting of pertussis immunity: Preclinical proof of concept (full text) "The limited durability of pertussis vaccine-induced protection requires novel approaches to reactivate immunity and limit pertussis resurgence in older children and adults. We propose that periodic boosters could be delivered using a novel epicutaneous delivery system (Viaskin®) to deliver optimized pertussis antigens such as genetically-detoxified pertussis toxin (rPT). "..." "Our observations therefore raise considerable hopes that this needle-free, adjuvant-free EDS may prove an efficient antigen-delivery-system for periodic boosting of pertussis immunity, addressing an unmet need. It could increase injection safety, be rapidly administered by non-injection-trained staff, improve compliance by reducing fears and injection-associated pain and address the unfounded but growing concerns related to the repeat use of aluminum adjuvants, especially during pregnancy. A proof-of-concept Phase I clinical study is thus in preparation."

June 24, 2015 - Asymptomatic transmission and the resurgence of Bordetella pertussis (pdf) "That there has been a rise in whooping cough incidence in many countries around the globe is irrefutable. The findings presented in Warfel et al., in conjunction with ours, have profound implications for the understanding of B. pertussis transmission dynamics and for vaccination policy. Specifically, our results would explain the negative outcomes found in recent studies of postnatal cocooning and would further complicate efforts to achieve herd immunity and possible eradication. Long-term solutions to B. pertussis vaccination are necessary, and new vaccines are in development. In the years before a new vaccine is ready for clinical use, other options are necessary for reducing incidence, including vaccination of pregnant women or potentially 'a switch back to wP' vaccination as a priming dose."

June 16, 2015 - Pertussis Across the Globe: Recent Epidemiologic Trends From 2000-2013. "It appears that pertussis incidence has increased in school-age children in North America and western Europe, where acellular pertussis vaccines are used, but an 'increase has also occurred' 'in some countries that use whole-cell vaccines."

June 2015 - Epidemic Pertussis and Acellular Pertussis Vaccine Failure in the 21st Century "Factors that I think are most important relating to DTaP vaccine failure are as follows: decay in antibody over time; a T helper (Th) 1/Th2 versus a Th1, Th17 cellular response; incomplete antigen package; incorrect balance of antigens in the vaccine; linked-epitope suppression; and the occurrence of pertactin-deficient Bordetella pertussis strains. Some, but not all, of these factors may also relate to Tdap failure over time."

June 2015 - Bordetella pertussis Is an Uncommon Pathogen in Children Hospitalized With Bronchiolitis During the Winter Season "All 4 were younger than 4 months; 2 met the Centers for Disease Control and Prevention definition of probable pertussis; and 3 had received at least 1 dose of an acellular pertussis vaccine. During the hospitalization, 2 had paroxysmal cough, 1 required intensive care unit care and the median length of stay was 13 days. Conclusions: Our data support that B. pertussis is an uncommon pathogen in U.S. children hospitalized with bronchiolitis in the winter. Making a diagnosis of pertussis can be challenging because the disease can be atypical and may not meet the Centers for Disease Control and Prevention definition of probable infection."

May 27, 2015 - Dynamics of Pertussis Transmission in the United States "States with predominantly annual cycles tended to have 'higher per capita birth rates, more household crowding, more children per family', and lower rates of school attendance than the states with multiennial cycles. Additionally, states that exhibited annual epidemics during 1938–1955 have had the highest recent (2001–2010) incidence, while those states that transitioned from annual cycles to multiennial cycles have had relatively low recent incidence. Our study provides an extensive picture of pertussis epidemiology in the United States dating back to the onset of vaccination, a back-story that could aid epidemiologists in understanding contemporary transmission patterns."

May 21, 2015 - Immunogenicity and reactogenicity of a decennial booster dose of a combined reduced-antigen-content diphtheria–tetanus–acellular pertussis and inactivated poliovirus booster vaccine (dTpa–IPV) in healthy adults (full text) "Pain was the most frequent solicited local adverse event (AE; ≥62.7% subjects) and fatigue the most frequent solicited general AE (≥18.5%). No serious AEs were reported during the study."..."This study was sponsored and funded by GlaxoSmithKline Biologicals SA. GlaxoSmithKline Biologicals SA was involved in all stages of the study conduct and analysis; and also took charge of all costs associated with developing and publishing the manuscript."

• Conflict of interest statement SK, KH and MK are employees of GSK
• and KH and MK declare having GSK stocks.
• NR was previously employed by GSK group of Companies.
• TFS has received honoraria from GSK as consultant, lecturer, member of advisory boards and for conducting clinical trials on behalf of his institution.

May 8, 2015 - Pertussis Resurgence Associated with Pertactin-Deficient and Genetically Divergent Bordetella Pertussis Isolates in Israel. "The proportion of pertactin-deficient isolates increased over time, 6.6% vs. 7.1% vs. 33.3% during 2005-2006, 2011-2012 and 2013-2014, p<0.03."

May 4, 2015 - Tdap Vaccine Effectiveness in Adolescents During the 2012 Washington State Pertussis Epidemic "Among adolescents who received all acellular vaccines (450 cases, 1246 controls), overall Tdap VE was 63.9% (95% confidence interval [CI]: 50% to 74%). VE within 1 year of vaccination was 73% (95% CI: 60% to 82%). At 2 to 4 years postvaccination, VE declined to 34% (95% CI: −0.03% to 58%). CONCLUSIONS: Tdap protection wanes within 2 to 4 years. Lack of long-term protection after vaccination is likely contributing to increases in pertussis among adolescents." Comment: Does this mean another booster? Oh wait then they can add another check point for vaccination along with kindergarten and 7th grade. Now, they can include the high schoolers. Then check again in college.

May 2015 - Identification of Pertussis-Specific Effector Memory T Cells in Preschool Children "At present, infant vaccinations with four aP vaccines in the first year of life result in pertussis-specific CD4+ and CD8+ effector memory T-cell responses that persist in children until 4 years of age and are higher than those in wP-primed children. The booster at 4 years of age is therefore questionable; t'his may be postponed to 6 years of age."

April 27, 2015 - Influenza and pertussis vaccination coverage in pregnant women "A documented vaccination coverage of 42.8% for influenza and 39.2% for pertussis was observed. Taking into account doses which were not documented, but administered according to the expectant mother, coverage for influenza would increase to 62% and for pertussis to 46%. The most important reasons for non-vaccination were the absence of a recommendation by medical staff (9.6%) and delay in vaccination (8.4%). The GP was the most important vaccinator. Pregnant women with a lower education and those with a foreign origin were more vulnerable for non-vaccination."

April 8, 2015 - Uptake of a government-funded pertussis-containing booster vaccination program for parents of newbabies in Victoria, Australia "Conclusion: Results of this survey indicated excellent uptake of the vaccine among both mothers and fathers under the Government-funded cocooning program. The findings are suggestive of an effective communications program designed to raise awareness of the risks of pertussis, and to promote availability of the funded vaccination program. The results may contribute to policy 'implementation of adult immunisation programs such as cocooning."

April 1, 2015 - While Waiting for Better Pertussis Vaccines, Let's Use the Ones We Have "We agree with the authors that their results reinforce the need for enhanced understanding of the correlates of protection against pertussis and for pertussis vaccines that induce more-durable immunity. While whole-cell pertussis vaccines provided more-durable protection, they were also associated with a high incidence of local and systemic side effects"

April 2015 - Predictors of Disease Severity in Children Hospitalized for Pertussis During an Epidemic "Conclusions: Most severe pertussis occurred in young, unimmunized infants, although severe disease was also observed in children >12 months of age and 'previously vaccinated children. Children admitted with pertussis with evidence of coinfection, history of prematurity or fever on presentation need close monitoring."

April 2015 - Seroprevalence of Pertussis in The Gambia: Evidence for Continued Circulation of Bordetella pertussis Despite High Vaccination Rates (full text) "Our data from a 2008 rural population cohort of over 1000 individuals aged between 2 and 90 years in The Gambia showed that 6% of individuals had antibody concentrations indicative of a pertussis infection within the last year (≥62.5 EU/mL). These data provide evidence that B. pertussis continues to be transmitted within this population despite high vaccination coverage.

March 31, 2015 - Why the Increase in Pertactin-Deficient Pertussis? (requires registration) "Patients who had received at least one dose of vaccine had a significantly higher odds of having PRN- B pertussis compared with unvaccinated patients (unadjusted odds ratio [OR], 3.2; 95% confidence interval [CI], 1.9-5.3). When patients were restricted to those aged 1 year or older and those who were age-appropriately vaccinated, the OR increased to 3.7 (unadjusted OR, 3.7; 95% CI, 1.9-7.1). The investigators concluded that the greater odds of having PRN- B pertussis when fully vaccinated according to schedule suggests that vaccinated persons have greater susceptibility to PRN- strains compared with PRN+ strains."

March 18, 2015 - Identification of pertussis specific effector memory T-cells in preschool children "Whooping cough remains a problem despite vaccination and worldwide resurging of pertussis is evident."..."At present infant vaccinations with four aP vaccines in the first year of life result in pertussis-specific CD4+ and CD8+ effector memory T-cell responses that persist in children until 4 years of age and are higher than in wP-primed children. The booster at 4 years of age is therefore questionable; this may be postponed to 6 years of age."

March 17, 2015 - Modulation of the CD4+ T cell response after acellular pertussis vaccination in the presence of TLR4 ligation "Whole cell pertussis (wP) vaccines are gradually being replaced by aluminum salt-adjuvanted acellular pertussis (aP) vaccines. These promote CD4+ T cell responses with a 'non-protective' Th2 component, while protective immune mechanisms to B. pertussis may rather involve long-lived Th1/Th17 type CD4+ T cells. Here we asked whether addition of a non-toxic meningococcal' LPS derivative, LpxL1, as adjuvant can favorably modulate the aP-induced pertussis-specific CD4+ T cell response in mice." Comment: LPS type adjuvants are know to cause autoimmune disease. See here for more.

March 2015 -Immunogenicity, Safety, and Antibody Persistence at 3, 5, and 10 Years Postvaccination in Adolescents Randomized to Booster Immunization with a Combined Tetanus, Diphtheria, 5-Component Acellular Pertussis, and Inactivated Poliomyelitis Vaccine Administered with a Hepatitis B Virus Vaccine Concurrently or 1 Month Apart (pdf) "The study was powered to evaluate immunogenicity, and so rare AEs or SAEs may not have been detected. Safety was assessed for '14 days' after each vaccination (except for SAEs, which were collected at any time through 30 days after the last vaccination) but this information was not collected throughout the 10-year follow-up. Only 62.8% of the participants could be assessed at the 10-year follow-up, and not all participants could be assessed at all time points. The determination of prior exposure to pertussis disease or pertussis vaccination was based on participant recall only and was not verified from medical records."

• This study was funded by Sanofi Pasteur, which also contributed to the study design, data collection, analysis and interpretation, review and editing of the manuscript (by Robert Lersch), and the decision to publish.
• J. Embree and B. Law have no conflicts of interest to declare. T. Voloshen and A. Tomovici are employees of Sanofi Pasteur

February 21, 2015 - Quantification of Vaccine-Induced Anti-Pertussis Toxin Secretory IgA Antibodies in Breast Milk: Comparison of Different Vaccination Strategies in Women. "Both antibody analytes were measured in breast milk samples of lactating women obtained eight to nine weeks postpartum to compare different maternal pertussis vaccination strategies: vaccination during pregnancy, shortly after or at delivery (cocoon), less than 5 years before delivery or more than 5 years before delivery."..."Conclusion: Vaccination against pertussis in the second/third trimester of pregnancy or immediately postpartum significantly increased the levels of anti-pertussis toxin sIgA in breast milk.

January 20, 2015 - Combating pertussis resurgence: One booster vaccination schedule does not fit all "Especially notable is the inability of booster schedules to alleviate resurgence when vaccines are leaky. Critically, our findings argue that the ultimate effectiveness of vaccine booster schedules will likely depend on correctly pinpointing the causes of resurgence, with misdiagnosis of the problem epidemiologically ineffective and economically costly."

January 15, 2015 - Demographic Evidence of Sex Differences in Vulnerability to Infectious Diseases (full text) "We directed a population observatory in Niakhar, Senegal, West Africa, in which a comprehensive demographic surveillance system (DSS) monitored causes of death, as well as family behavior. In this population, there was no evidence of any differential behavior between boys and girls, as is generally true in African countries. But mortality was higher for girls than for boys for selected diseases (measles and pertussis), despite similar incidences. Furthermore, a randomized controlled trial of the Edmonston-Zagreb 'high-titer measles vaccine demonstrated a higher susceptibility to measles virus among girls."

January 5, 2015 - Duration of Pertussis Immunity After DTaP Immunization: A Meta-analysis "'Pertussis incidence is increasing, possibly due to the introduction of acellular vaccines, which may have decreased the durability of immune response. We sought to evaluate and compare the duration of protective immunity conferred by a childhood immunization series with 3 or 5 doses of diphtheria-tetanus-acellular pertussis (DTaP)."..."Disclosure: Fisman reports financial ties with GlaxoSmithKline, Merck, Novartis and Sanofi Pasteur.

January 1, 2015 - What predicts postpartum pertussis booster vaccination? A controlled intervention trial "A cocooning strategy for pertussis vaccination can be highly effective when partially implemented within maternity hospitals, with information accompanied by a funded vaccine. Mothers were highly receptive to vaccination in the postnatal ward: facts about pertussis were as effective as message-framing in promoting a high uptake of 70%." Comment: Keep finding more ways to push vaccines.

December 8, 2014 - Genomic analysis of isolates from the UK 2012 pertussis outbreak reveals that vaccine antigen genes are unusually fast evolving "Importantly, we demonstrate that acellular vaccine antigen encoding genes are evolving at higher rates than other surface protein encoding genes. This was true even prior to the introduction of pertussis vaccines, but has become more pronounced since the introduction of the current acellular vaccines. The fast evolution of vaccine antigen genes has serious consequences for the ability of current vaccines to continue to control pertussis."

December 5, 2014 - CDC MMWR Pertussis Epidemic — California, 2014 "Among the 83% of adolescent cases aged 14–16 years with known vaccination histories, only 2.2% reported never receiving any doses of pertussis-containing vaccine. Of those vaccinated adolescents with complete data, 87% had previously received the Tdap booster vaccine, and the median length of time since prior Tdap dose was 3 years (range = 0–7 years)."

December 2, 2014 - Seizures, Encephalopathy, and Vaccines: Experience in the National Vaccine Injury Compensation Program "The VICP retrieved 165 claims that had sufficient clinical information for review. Approximately 80% of these 'alleged' an injury associated with whole-cell diphtheria, pertussis (whooping cough), and tetanus or tetanus, diphtheria toxoids, and acellular pertussis vaccine. Pre-existing seizures' were found in 13% and abnormal findings on a neurologic examination 'before' the alleged vaccine injury in 10%. A final diagnostic impression of seizure disorder was established in 69%, of whom 17% (28 patients) had myoclonic epilepsy, including possible severe myoclonic epilepsy of infancy. Specific conditions not caused' by immunization, such as tuberous sclerosis and cerebral dysgenesis, were identified in 16% of subjects."

December 2, 2014 - Seroprevalence of Pertussis in The Gambia: Evidence for Continued Circulation of Bordetella pertussis Despite High Vaccination Rates."These data provide evidence that B. pertussis is being transmitted within this population despite high vaccination coverage. Re-infection may occur implying that immunity from childhood vaccination may not be life-long. In the absence of data on actual clinical cases of pertussis, seroprevalence studies remain valuable tools to assess the transmission dynamics of B.pertussis."

November 20, 2014 - Pertactin deficient Bordetella pertussis present a better fitness in mice immunized with an acellular pertussis vaccine "Recently, it has been reported that B. pertussis clinical isolates loose the production of this adhesin in regions reaching high vaccine coverage with vaccines targeting this virulence factor. We here demonstrate that isolates not producing pertactin are capable of sustaining longer infection as compared to pertactin producing isolates in an in vivo model of acellular pertussis immunization. Loosing pertactin production might thus provide a selective advantage to these isolates in this background, which 'could account for the upraise in prevalence of these pertactin deficient isolates in the population."

October 21, 2014 - Characterization of the key antigenic components of pertussis vaccine based on outer membrane vesicles "The epidemiological situation of pertussis points out the need to develop new vaccines"

October 14, 2014 - Anti-pertussis antibody kinetics following DTaP-IPV booster vaccination in Norwegian children 7–8 years of age (full text) "This study indicates that the currently used acellular pertussis vaccines induce moderate immune responses to the pertussis antigens and that the antibodies wane within few years after the booster. This lack of sustained immune response may partly be responsible for the increased number of pertussis cases observed in this age group during the last years."

October 9, 2014 - Pertactin-negative B. pertussis strains: evidence for a possible selective advantage "Conclusions. The significant association between vaccination and isolate pertactin produciton suggests the likelihood of having reported disease caused by PRN- compared to PRN+ strains is greater in vaccinated persons. Additional studies are needed to assess whether 'vaccine effectiveness is diminished against PRN- strains."

October 2014 - Molecular Epidemiology of the Pertussis Epidemic in Washington State in 2012 "This study provides evidence for the continued predominance of MLVA 27 and prn2-ptxP3-ptxA1 alleles, along with the reemergence of the fim3-1 allele. Our results indicate that the Bordetella pertussis population causing this epidemic was diverse, with a few molecular types predominating. The PFGE, MLVA, and MLST profiles were consistent with the predominate types circulating in the United States and other countries. For prn, several mutations were present in multiple molecular types."

September 30, 2014 - Bordetella pertussis: an underreported pathogen in pediatric respiratory infections, a prospective cohort study (pdf) "In accordance with other reports, we observed that paroxysmal cough is not specific for pertussis. In the unsuspected pertussis group less children suffered from paroxysmal cough and more children had only symptoms of an URTI. This suggests that the current clinical case definitions of pertussis are not sufficient for diagnosing all pertussis cases. Especially the 'atypical and mild infections', more 'f'requently 'seen in unvaccinated children', are missed."

September 15, 2014 - Seroprevalence of IgG antibodies to pertussis toxin in children and adolescents in Estonia "The serologic method is not suitable for diagnosing pertussis in instances when the last pertussis immunisation was less than one year ago. The relatively high proportion of subjects with undetectable anti-PT IgG levels and the relatively low rate of officially reported pertussis cases suggest that 'low antibody levels do not necessarily indicate the absence of protection."

August 18, 2014 - Pertussis Resurgence and Vaccine Uptake: Implications for Reducing Vaccine Hesitancy "Seventy-seven percent of parents of young children report concerns about vaccines, such as the number of vaccines or doses given simultaneously or before age two, what ingredients are contained in vaccines, or if there are associations with adverse outcomes such as autism and other chronic diseases. Some have gone so far as to identify a “vaccine crisis in confidence."

August 18, 2014 - Impact of a Pertussis Epidemic on Infant Vaccination in Washington State "Washington State experienced a pertussis epidemic from October 2011 to December 2012. There was wide variation in incidence by county. The objectives of this study were to determine how the pertussis epidemic affected infant vaccination in Washington State and whether the incidence in counties modified this effect."..."A statewide pertussis epidemic does not appear to have significantly changed the proportion of infants who were UTD with a pertussis-containing vaccine."

July 16, 2014 - Molecular Epidemiology of Pertussis Epidemic — Washington State, 2012 "Four different prn mutations accounted for the 76% of isolates exhibiting pertactin-deficiency. PFGE provided the highest discriminatory power (D=0.87) and was found to be a more powerful typing method than MLVA and MLST combined (D=0.67). This study provides evidence for the continued predominance of MLVA 27 and prn2-ptxP3-ptxA1, along with the reemergence of the fim3-1 allele. Our results indicate that the B. pertussis population causing this epidemic was diverse, with a few molecular types predominating."

July 11, 2014 - Safety of pertussis vaccination in pregnant women in UK: observational study (full text) "Over 700 000 women in the third trimester of pregnancy were to be offered vaccination in the UK over the first year. Given relatively high background rates for several adverse outcomes during pregnancy, particularly stillbirth, it was inevitable that such events would occur in 'temporal association with vaccination, regardless of causality."

July 2014 - Pertussis Toxin Improves Immune Responses to a Combined Pneumococcal Antigen and Leads to Enhanced Protection against Streptococcus pneumoniae "The combination of PspA5 with wild-type or mutant 'Bordetella pertussis strains or with purified components showed that the pertussis toxin (PT)-containing formulations induced the highest levels of antibodies and protection. This suggests that the adjuvant activity of wP in the PspA5 model is mediated at least in part by PT." Comment: The wild type pertussis toxin is know to adverse events, especially seizures. See here

July 2, 2014 - Evaluation of the Impact of a Pertussis Cocooning Program on Infant Pertussis Infection. "Conclusions: Postpartum immunization and cocooning did not reduce pertussis illness in infants <= 6 months of age. Efforts should be directed towards increasing Tdap immunization during pregnancy, combined with cocooning, to reduce life-threatening young infant pertussis." Comment: So vaccinate pregnant women? Some information from the FDA on this subject. "The FDA is continuing its efforts to reduce the exposure of infants, children, and pregnant women to mercury from various sources. Discussions with the manufacturers of influenza virus vaccines (which are now routinely recommended for pregnant women and children 6-23 months of age) regarding their capacity to potentially increase the supply of thimerosal-reduced and thimerosal-free presentations are ongoing." View here

July 2014 - Occurrence of 3 Bordetella Species During an Outbreak of Cough Illness in Ohio: Epidemiology, Clinical Features, Laboratory Findings and Antimicrobial Susceptibility "All 3 Bordetella species, Bp, Bh and Bpp, were detected during on outbreak of pertussis-like cough illness. There were noted differences in age and seasonality, but clinical features at the time of presentation 'did not allow clear differentiation of these infections. Comment: Bordetella parapertussis may increase in the vaccinated. See here "An acellular whooping cough vaccine actually enhances the colonization of Bordetella parapertussis in mice; pointing towards a rise in B. parapertussis incidence resulting from acellular vaccination, which may have contributed to the observed increase in whooping cough over the last decade."

June 24, 2014 - Whooping cough in school age children presenting with persistent cough in UK primary care after introduction of the preschool pertussis booster vaccination: prospective cohort study "The risk of pertussis was more than three times higher (21/53; 40%, 26% to 54%) in children who had received the preschool pertussis booster vaccination seven years or more previously than in those who had received it less than seven years previously (20/171; 12%, 7% to 17%). The risk of pertussis was similar between children who received five and three component preschool pertussis booster vaccines (risk ratio for five component vaccine 1.14, 0.64 to 2.03). Four of six children in whom cough frequency was measured coughed more than 400 times in 24 hours."

June 5, 2014 - Estimating the Effectiveness of Tdap Vaccine for Preventing Pertussis: Evidence of Rapidly Waning Immunity and Differences in Effectiveness by Tdap Brand "Our results demonstrate waning immunity following Tdap vaccination with either brand. Boostrix was more effective than Adacel in preventing pertussis among our cohort, but these findings may not be generalizable to adolescent cohorts that received different DTaP vaccines and should be further examined in studies that include childhood DTaP history."

June 5, 2014 - B-cell responses after intranasal vaccination with the novel attenuated Bordetella pertussis vaccine strain BPZE1 in a randomized phase I clinical trial "Despite high vaccination coverage, pertussis is still a global concern in infant morbidity and mortality, and improved pertussis vaccines are needed. A live attenuated Bordetella pertussis strain, named BPZE1, was designed as an intranasal vaccine candidate' and has recently been tested in man in a phase I clinical trial."

June 2014 - Oral Fluid Testing for Pertussis, England and Wales, June 2007–August 2009 "Successful programs for vaccination of pregnant women would directly reduce the number of cases among infants <3 months of age. If high levels of activity persist in other age groups, however, increased risk of acquiring infection during infancy would also persist." Comment: More pressure to vaccinate pregnant women.

May 2014 - Antibody and Cell-mediated Immunity to Pertussis 4 Years After Monovalent Acellular Pertussis Vaccine at Birth (full text) "Longer term theoretical concerns of neonatal pertussis vaccination include reduced responsiveness to booster doses of pertussis (immune hyporesponsiveness), interference with concomitant antigen responses and increased reactogenicity following booster doses."

April 25, 2014 - Vaccine preventable diseases: Time to re-examine global surveillance data? "In 2012, highest pertussis case numbers and incidence were reported from high income countries with high vaccine coverage, discordant with countries that had low vaccine coverage. Use of laboratory diagnostics for pertussis cases varied among countries. In contrast, highest reported numbers of measles cases and incidences tended to occur in low income countries. These observations imply poor quality global surveillance data for some VPDs, limiting capacity for monitoring global epidemiology or making vaccination policy decisions.

April 1, 2014 - Humoral and B-cell memory responses in children five years after pertussis acellular vaccine priming "The pre-school booster dose restores the percentage of protected children above 50%. In conclusion our data underline the importance of giving a booster dose 5 years after primary vaccination and suggest the need for a new vaccine able to induce a long lasting protective response."

April 1, 2014 - Changing Pertussis Epidemiology: Everything Old is New Again (full text) "In the early days of vaccination, outbreaks of pertussis were observed among vaccinated children within just a few years of vaccination; however, disease was milder. This suggested that immunity from vaccination waned and that protection against infection was less complete than against the severest manifestations of disease. A final critical observation is that the cyclic nature of pertussis epidemics remained largely unchanged after the widespread use of vaccination. Interepidemic periods of 3–5 years persisted, suggesting that although vaccination prevented disease or at least its severest manifestations, transmission of infection continued.

April 1, 2014 - Immune Responses to Pertussis Vaccines and Disease (full text) "(1) acellular vaccines are immunogenic, but responses vary by vaccine; (2) pertussis antibody levels rapidly wane but promptly increase after vaccination; (3) whole-cell vaccines vary in immunogenicity and efficacy;"..."Despite these findings, challenges remain in understanding the immune response to pertussis vaccines."

April 1, 2014 - Pertussis Resurgence: Perspectives From the Working Group Meeting on Pertussis on the Causes, Possible Paths Forward, and Gaps in Our Knowledge (full text) "Members of the working group voiced the opinion that additional studies are needed to determine whether this approach holds promise, to determine whether the vaccine has a good safety profile in this age group, and to ascertain that such a practice does not misdirect the immune system in an unintended way. Moreover, this approach would likely require development of an acellular-pertussis-only vaccine that lacks the diphtheria and tetanus components of the combined diphtheria, tetanus, and acellular pertussis (pediatric formulation) vaccine.

April 1, 2014 - Pertussis Vaccine Trials in the 1990s (full text) "As the trials in the 1990s were concluding, however, the following unanswered questions about the DTaP vaccines remained: Is there an optimum number of B. pertussis components in the acellular vaccine, and if so, what is it? Are there optimum amounts of each antigen? Is there an optimum schedule for DTaP administration? What is the duration of protection that they provide? The immunological correlates of protection from pertussis were also unknown during the trials in the 1990s and remain so today."

April 1, 2014 - Possible Options for New Pertussis Vaccines (full text) "Change in delivery system: All the vaccines discussed above involve parenteral administration of a combination of B. pertussis antigens with at least 1 adjuvant component and induce essentially systemic immune responses, whereas B. pertussis infection is a strictly respiratory mucosal infection. The inherent limitations in the nature of the immune responses generated by the current aP vaccines have encouraged substantial interest in other delivery systems. Possible approaches include (1) a live attenuated B. pertussis strain for intranasal administration;

April 1, 2014 - Clinical Evaluation of Pertussis Vaccines: US Food and Drug Administration Regulatory Considerations (full text) "Unlike whole-cell pertussis vaccines, which contain suspensions of killed Bordetella pertussis organisms, less reactogenic acellular pertussis vaccines comprise ≥1 purified antigens that play a role in pertussis pathogenesis. Pertussis toxin (inactivated), filamentous hemagglutinin, pertactin, and fimbriae induce antibodies that contribute to protection in an animal model, and natural infection with B. pertussis in humans induces antibodies to each of these antigens. However, 'there is no scientifically well-established immunologic marker of protection for pertussis'. The protective mechanism of the vaccines, probably multifactorial, has not been fully elucidated.

April 2014 - Rapid Increase in Pertactin-deficient Bordetella pertussis Isolates, Australia "Multiple factors probably contributed to the resurgence of pertussis in high-income countries that had long-standing pertussis immunization programs. These factors include waning immunity (exacerbated by the change from WCVs to ACVs and, in Australia, cessation of the booster vaccination at 18 months of age) and increased use of more sensitive diagnostic tests, such PCR. An additional possible contributing factor is evolution of B. pertussis through 'vaccine-driven adaptation. The most prominent recent changes in circulating B. pertussis strains are polymorphisms within genes encoding 2 of the 3 main virulence factors (ptx and prn) contained in the vaccine. Variations have also been reported in ptxP, the promoter of the ptx operon."

February 12, 2014 - Substantial gaps in knowledge of Bordetella pertussis antibody and T cell epitopes relevant for natural immunity and vaccine efficacy "The recent increase in whooping cough in vaccinated populations has been attributed to waning immunity associated with the acellular vaccine."..."Moreover, there are a 'limited number of studies 'defining epitopes from natural infection versus whole cell or acellular/subunit vaccines. The relationship between epitope location and structural features, as well as antigenic drift (SNP analysis) was also investigated. We conclude that the cumulative data is yet insufficient to address many fundamental questions related to vaccine failure and this underscores the need for further investigation of B. pertussis immunity at the molecular level."

February 2014 - Prevalence and Molecular Characterization of Pertactin-Deficient Bordetella pertussis in the United States "Bordetella pertussis isolates lacking pertactin, a key antigen component of the acellular pertussis vaccine, have been observed, suggesting that B. pertussis is losing pertactin in response to vaccine immunity. Screening of 1,300 isolates from outbreak and surveillance studies (historical isolates collected from 1935 up to 2009, isolates from the 2010 California pertussis outbreak, U.S. isolates from routine surveillance between 2010-2012, and isolates from the 2012 Washington pertussis outbreak) by conventional PCR and later by Western blotting and prn sequencing analyses ultimately identified 306 pertactin-deficient isolates. Of these pertactin-deficient strains, 276 were identified as having an IS481 in the prn gene (prnIS481 positive)."

February 2014 - Antibody Responses to Bordetella pertussis Fim2 or Fim3 following Immunization with a Whole-Cell, Two-Component, or Five-Component Acellular Pertussis Vaccine and following Pertussis Disease in Children in Sweden in 1997 and 2007 "Those who received DTaP5 showed a large rise in anti-Fim2 IgG, reflecting the predominant Fim2 serotype at the time. In contrast, those who received DTwP showed an equal rise in anti-Fim2 and anti-Fim3 IgG concentrations, indicating that DTwP may provide a more efficient priming effect for a Fim3 response following contact with B. pertussis.

January 16, 2014 - Different effects of whole cell and acellular vaccines on Bordetella transmission "Finally, whole-cell vaccination was able to prevent transmission, however an acellular vaccine that effectively controls disease failed to control shedding and transmission."

January 8, 2014 - A Phase I Clinical Study of a Live Attenuated Bordetella pertussis Vaccine - BPZE1; A Single Centre, Double-Blind, Placebo-Controlled, Dose-Escalating Study of BPZE1 Given Intranasally to Healthy Adult Male Volunteers (pdf) "A genetically modified B. pertussis strain has therefore been constructed as a vaccine candidate to be administered by the nasal route, in order to mimic natural infection without inducing disease."..."With a few exceptions, most attenuated live vaccines are viral vaccines. BPZE1 is the first 'live attenuated' bacterial vaccine specifically designed for the respiratory tract tested in humans. Since this was the first-in-man study of BPZE1, the number of volunteers was limited, and the primary objective of the study was the local and general safety assessment."

January 4, 2014 - Intention to accept Bordetella pertussis booster vaccine during pregnancy in Mexico City "Over 80% of respondents would accept pertussis vaccination if recommended by an obstetrician-gynecologist. The most frequently selected reasons to refuse pertussis vaccination were concerns that the vaccine might harm the unborn baby or pregnant woman."

January 4, 2014 - Acellular pertussis vaccine based on outer membrane vesicles capable of conferring both long-lasting immunity and protection against different strain genotypes "To improve the disease control, a new generation of vaccines capable to overcome those weaknesses associated to the current vaccines need to be developed."... "All results presented here showed that TdapOMVsBpPagL is an interesting formulation to be considered for the development of novel acellular 'multi-antigen' vaccine.'

January 2014 - Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model (full text) "Acellular Vaccines Fail to Prevent Infection Following Natural Transmission."

December 23, 2013' - Attitudes, knowledge and perceptions towards whooping cough and pertussis vaccine in hospitalized adults "The results showed that even though there is general acceptance of prevention by vaccines, there is low awareness about pertussis vaccination. This lack of knowledge presents a barrier against pertussis vaccination thus it is imperative that any future adult immunisation policy recommendations around pertussis vaccine include awareness programs in the target population."

December 17, 2013 - Different T cell memory in preadolescents after whole-cell or acellular pertussis vaccination (full text) "Although the time since the last booster vaccine was significantly longer for wP-compared to aP-vaccinated children, their proliferation capacity in response to antigenic stimulation was comparable, and more children had a detectable cytokine response after wP- compared to aP-vaccination. This study supports at the immunological level recent epidemiological studies indicating that infant vaccination with wP induces longer lasting immunity than vaccination with aP-vaccines."

December 11-12 2013 - Meeting of the Board of Scientific Counselors, Office of Infectious Diseases Centers for Disease Control and Prevention Tom Harkins Global Communication Center Atlanta, Georgia (pdf) "Resurgence of Pertussis. As reported at the May 2013 BSC meeting, the recent resurgence in pertussis cases has been associated with waning immunity over time in persons who received the acellular pertussis vaccine (which is administered as the pertussis component of DTaP vaccine). However, a recent study suggests another explanation for decreased vaccine effectiveness: an increase in Bordetella pertussis isolates that lack pertactin (PRN)--a key antigen component of the acellular pertussis vaccine."

December 9, 2013 - The role of health economic analyses in vaccine decision "More recently, the US Institute of Medicine has recommended that health economic considerations play a primary role in the prioritization of future vaccine for development. However, such analyses can be biased towards vaccines that provide economic benefit rather than those that reduce severe morbidity and mortality."..." Thus the use of cost effectiveness analyses as a ‘gating criteria’ to decide which vaccines should be developed or routinely used runs the risk of transforming vaccines into primarily a tool for achieving cost savings within the health care system rather than a public health intervention targeting human suffering, death and disability."

November 20, 2013 - Prevalence and molecular characterization of pertactin-deficient Bordetella pertussis in the US "Pertussis has made a striking resurgence in the US, returning to record numbers of reported cases last observed in the 1950s. Bordetella pertussis isolates lacking pertactin, a key antigen component of the acellular pertussis vaccine, have been observed, suggesting that B. pertussis is losing pertactin in response to vaccine immunity."..."Pertactin-deficient isolates increased substantially to over 50% in 2012. Sequence analysis of pertactin-deficient isolates revealed various types of mutations in the prn gene, including two deletions, single nucleotide substitutions resulting in a stop codon, an inversion in the promoter, and a single nucleotide insertion resulting in a frame shift mutation."

November 2013 - Influenza and Pertussis Vaccination Coverage Among Privately Insured Women of Reproductive Age "Among insured women of reproductive age, there is a need for interventions to increase Tdap and influenza vaccination uptake. Further research is needed to understand and address disparities in influenza vaccination coverage in this population."

October 30, 2013 - Vaccination of health care workers against pertussis: Meeting the need for safety within hospitals "In high risk situations, e.g. in pregnant health care workers and those in contact with infants <6 months of age, antibiotic prophylaxis should also be recommended to previously immunised, pertussis exposed health care workers. Local programmes based on education, conviction and common sense''''' should be implemented for health care workers '''''rather than mandatory pertussis immunisation. In addition, health care workers need to be informed and regularly reminded about the impact of exposure to pertussis."

October 22, 2013 - Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model "The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines."

October 21, 2013 - Infant Hospitalizations for Pertussis Before and After Tdap Recommendations for Adolescents "Observed hospitalization rates for pertussis among infants were significantly lower than expected in 2008, 2009, and 2011, but in 2010 the observed and expected rates of hospitalization were not significantly different. CONCLUSIONS: Adolescent Tdap vaccination appears to be partially effective in preventing pertussis hospitalizations among infants. However, '''''broader Tdap immunization coverage may be necessary to achieve sustainable reductions in infant pertussis burden."

October 17, 2013 - Respiratory Diphtheria "A 13-year-old girl with a history of incomplete childhood immunization (she had received only the first of three doses of the diphtheria–pertussis–tetanus vaccine)..."The throat culture was positive for Corynebacterium diphtheriae. The patient recovered without any major complication, with the bull neck disappearing within 1 week after the initiation of treatment."

September 30, 2013 - Nonmedical Vaccine Exemptions and Pertussis in California, 2010 (full text) "This analysis is subject to several limitations. NME data from California do not contain specific data on which vaccine(s) or dose(s) were not received by a child with a NME, and it is possible that some children with a NME were completely vaccinated against pertussis. Future studies should attempt to analyze varying rates of vaccine avoidance for specific antigens to determine the magnitude of impact within populations with high NMEs. Furthermore,NME data from kindergarten entry are a 1-time measurement and only a proxy for community-level vaccination coverage and immunity.

• " Ms Atwell is a former employee of the California Department of Public Health and also received compensation in 2011 and 2012 for contract work relating to new vaccine introduction from the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunization) and PATH.

• Dr Halsey has received research grants from Crucellfor studies of vaccines in Guatemala and has served on data and safety monitoring review boards for Merck and Novartis on vaccine studies. Dr Halsey has received consultant fees for assistance with patent lawsuit for GlaxoSmithKline."

July 17, 2013 - Effectiveness of pertussis vaccines for adolescents and adults: case-control study (full text) "Reduced acellular pertussis (Tdap) vaccines are moderately effective, reducing the risk of pertussis by about 60%, and this effect is not diminished in those who received only acellular rather than whole cell vaccines, as infants. Though these vaccines provide protection, more effective vaccines may be necessary to prevent further outbreaks" Comment: Teen DTap vaccines only about 60% effective...just a little better than a coin toss yet it's pushed on all the kids who have to live with any long term side effects.

July 8, 2013 - Seroprevalance of pertussis antibodies in maternal and cord blood of preterm and term infants "Anti-pertussis antibody levels were generally low in infant–mother pairs and would not be adequate to confer protection until the onset of primary immunization series. Transplacental anti-pertussis antibody transfers and antibody levels were lower in the cord blood of preterm infants, especially in those <32 weeks. These findings support the rationale for maternal immunization, which in combination with cocooning, could be a better option for preterm infants."

June 28, 2013 - Novel vaccine formulations against pertussis offer earlier onset of immunity and provide protection in the presence of maternal antibodies "New vaccines are needed that can provide early life and long-lasting protection of infants. Vaccination at an early age, however, is problematic due to the interference with maternally derived antibodies (MatAbs) and the bias towards Th2-type responses following vaccination."

June 3, 2013 - A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens "Compared to natural infection, responses to PT after vaccination with the tested vaccines are smaller in magnitude and tend to decay slightly faster. When present in vaccines, FHA and Prn tend to produce high peak levels, higher than those in naturally infected patients, but these decay faster. As expected, the Dutch whole cell vaccine produced lower antibody responses than the acellular vaccines. This model allows a better comparison of the kinetics of vaccine induced antibody responses and after natural infection over a long follow up period."

June 1, 2013 -Deferring, forgoing vaccination to avoid seizures is not always necessary "Seizures as a potential complication of vaccination were first described in isolated case reports about early diphtheria, tetanus and pertussis (DPT) vaccines and, more recently, in population and case-control studies. Studies have shown an increased risk of seizures associated with fever, but not epilepsy, within a few days of DTP vaccination. Fewer children have seizures within a few days of receiving diphtheria and tetanus toxoids and accellular pertussis (DTaP) vaccine compared to DTP vaccine (one per 15,000 or fewer children who receive DTaP vs. one per 1,750-4,000 children who receive DTP)."..."The risk of febrile seizures also is increased five to 12 days after the first dose of measles, mumps, rubella, varicella (MMRV) vaccine."

May 20, 2013 - Comparative Effectiveness of Acellular Versus Whole-Cell Pertussis Vaccines in Teenagers "We compared 138 PCR-positive cases with 899 PCR-negative and 54 339 KPNC-matched controls. Teenagers who had received 4 DTwPs were much less likely to be pertussis PCR-positive than those who had received 4 DTaPs (odds ratio 5.63, 95% confidence interval 2.55–12.46) or mixed DTwP/DTaP vaccines (odds ratio 3.77, 95% confidence interval 1.57–9.07). Decreasing number of DTwP doses was significantly associated with increased pertussis risk (P < .0001). CONCLUSIONS: Teenagers who received DTwP vaccines in childhood were more protected during a pertussis outbreak than were those who received DTaP vaccines."

April 4, 2013 - Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine (full text) "Although Pa have significantly improved safety profiles over Pw that they replaced and protect a significant percentage of children against a life threatening disease, there is an increasing incidence of pertussis in many developed countries. In an attempt to limit the spread of B. pertussis, a number of countries have introduced booster vaccinations with Pa for 5–6 year olds, adolescents and even adults. However, a recent report has suggested protection from whooping cough in children that had received 5 doses of Pa is relatively short-lived and wanes substantially each year. Furthermore, repeated boosting of Th2 or Th17 responses may not be desirable, since these responses can mediate hypersensitivity/allergy or autoimmunity when directed against allergens or self-antigens respectively. Indeed there is already evidence of hypersensitivity reactions in pre-school children following the fifth dose of Pa. The corollary to this is that efficacy of a vaccine that relies heavily on IL-17A to confer protective immunity may be compromised in patients treated with IL-17A targeted drugs, which are in late stage clinical development for autoimmune diseases.

March 13, 2013 - Reduced Risk of Pertussis Among Persons Ever Vaccinated With Whole Cell Pertussis Vaccine Compared to Recipients of Acellular Pertussis Vaccines in a Large US Cohort "Receipt of 1 or more wP doses markedly augmented the durability of immunity from subsequent aP doses. It appears that a wholly acellular pertussis vaccine series is significantly less effective and durable than one that contains the traditional whole cell vaccine."

March 11, 2013 - Waning Immunity to Pertussis Following 5 Doses of DTaP (pdf) "This evaluation reports steady increase in risk of pertussis in the years after completion of the 5-dose DTaP series. This rise is likely attributable in part to waning immunity from DTaP vaccines. Continuing to monitor disease burden and vaccine effectiveness in fully vaccinated children in coming years will be important to assess ongoing risk as additional cohorts vaccinated solely with acellular pertussis vaccines are introduced."... "Pertussis continues to be the most poorly controlled bacterial vaccine-preventable disease in this country, despite high rates of DTaP coverage."

February 1, 2013 - Safety of a Tetanus-Diphtheria-Acellular Pertussis Vaccine When Used Off-Label in an Elderly Population "Although there is a small increased risk of medically attended inflammatory or allergic events in 1–6 days following Tdap compared to other time periods, it is no more common than that following Td. This study provides empirical safety data suggesting that immunizing adults aged ≥65 years with Tdap to reduce the risk of pertussis in the elderly and their contacts should not have untoward safety consequences."

November 26, 2012 - Re-emergence of diphtheria and pertussis: Implications for Nigeria "The recent reported increases in the incidence of these two diseases in countries, which maintain high childhood vaccination coverage is a source of concern not only to these countries but also for developing countries with weak immunization programmes. Nigeria for example reported 11,281 cases of pertussis, the second highest number of cases worldwide in 2009."

November 26, 2012 - Improved protocols for histamine sensitization testing of acellular pertussis vaccines "The histamine sensitization test is a widely used method for measuring the residual toxicity of pertussis toxin in acellular pertussis vaccines Although it has been used as a routine assay for decades, the current protocols are difficult to standardize because the test results vary considerably and are based on several factors, including mouse strain, age and sex. In this study, we observed that mice of strains CD1, ddY and C57/BL6 were sufficiently sensitive to pertussis toxin among six mice strains tested and that aged male mice were more sensitive to pertussis toxin than younger or female mice."

November 8, 2012 - U.S. Postlicensure safety surveillance for adolescent and adult tetanus, diphtheria and acellular pertussis vaccines: 2005–2007 "A total of 2090 reports (7% were serious; 55% listed Tdap alone) involving Tdap vaccinees were submitted to VAERS May 2005–June 2007. The crude reporting rate was 10.2 per 100,000 vaccine doses distributed. The median age of vaccinees was 22 years, and the female to male ratio was about 2 to 1. The majority of reports described common local and systemic signs and symptoms, such as injection site reactions, fever, and headache. Rarely reported adverse events included myopericarditis, demyelinating diseases of the central nervous system, Guillain–Barré Syndrome, syncope, encephalopathy/encephalitis, seizure, Bell's palsy, anaphylaxis, and thrombocytopenia."

November 6, 2012 - Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection "Although immunity after infection seems to persist longer than that after vaccination, the exact mechanism(s) is not known."..."Our results suggest that there may be difference in quality and quantity of antibodies to PT after vaccination and after infection. Furthermore, AI could be a help for vaccine studies."

November 6, 2012 - The importance of pertussis in older adults: A growing case for reviewing vaccination strategy in the elderly "However, current knowledge of burden of disease is limited largely to passive surveillance data with little well-designed active surveillance to better ascertain the true burden of pertussis in the elderly, to inform vaccination strategies. The current review aims to identify gaps in knowledge to inform policy considerations relating to pertussis vaccination among the elderly.

November 1, 2012 - Underestimating the Safety Benefits of a New Vaccine: The Impact of Acellular Pertussis Vaccine Versus Whole-Cell Pertussis Vaccine on Health Services Utilization "The authors estimated that approximately 90 emergency room visits and 9 admissions per month were avoided by switching to the acellular vaccine, which is a 38-fold higher impact than when they considered only admissions for febrile and afebrile convulsions. Future analyses comparing vaccines for safety should examine specific endpoints and general health services utilization."

October 15, 2012 - Lack of Cross-protection against Bordetella holmesii after Pertussis Vaccination "Our data indicate that B. holmesii is circulating in Massachusetts and that B. pertussis vaccination confers little protection against B. holmesii. Careful B. holmesii surveillance is required to better evaluate its prevalence and transmission. B. holmesii genome sequencing may identify novel virulence determinants to explain its emergence in the human population and guide effective vaccine design."

August 30, 2012 - Epidemic Pertussis in 2012 — The Resurgence of a Vaccine-Preventable Disease (full text) "Finally, we should consider the potential contribution of genetic changes in circulating strains of B. pertussis. It is clear that genetic changes have occurred over time in three B. pertussis antigens — pertussis toxin, pertactin, and fimbriae. In fact, changes in fimbrial agglutinogens related to vaccine use were noted about 50 years ago. Studies in the Netherlands and Australia have suggested that genetic changes have led to vaccine failures, but many people question these findings. If genetic changes had increased the rates of vaccine failure, one would expect to see those effects first in Denmark, which has for the past 15 years used a vaccine with a single pertussis antigen (pertussis toxin toxoid). To date, however, there is no evidence of increased vaccine failure in Denmark."

August 29, 2012 - International Workshop on Alternatives to the Murine Histamine Sensitization Test (HIST) for Acellular Pertussis Vaccines: State of the Science and the Path Forward "Regulatory authorities require safety, potency, and purity testing prior to the release of each production lot of pertussis or pertussis antigen-containing vaccines. The murine histamine sensitization test (HIST) is a key safety test used to monitor residual levels of pertussis toxin (PTx) in vaccines. This test is performed to ensure that PTx has been effectively inactivated before release of vaccines (Corbel and Xing, 2004). However, such testing may involve large numbers of mice, some of which can experience significant unrelieved pain and distress. In addition, the HIST has technical challenges requiring frequent retesting, thereby increasing vaccine testing 'expense and animal usage."

August 15, 2012 - Epidemic Pertussis in 2012 — The Resurgence of a Vaccine-Preventable Disease (full text) "Recent data from California also suggest waning of vaccine-induced immunity after the fifth dose of DTaP vaccine.5 Certainly the major epidemics in 2005, in 2010, and now in 2012 suggest that failure of the DTaP vaccine is a matter of serious concern."

May 9, 2012 - Functional deficits of pertussis-specific CD4+ T Cells in Infants Compared to Adults Following DTaP Vaccination "Understanding the immune responses that explain why infants require multiple doses of pertussis vaccine to achieve protection against infection is a high priority."..."Moreover, a significantly higher percentage of infant's functional CD4+ T cells were restricted to CD45RA-CCR7+CD27+ phenotype, consistent with early stage differentiated pertussis-specific memory CD4+ T cells. We show for the first time that 'DTaP vaccination induced CD4+ T cells in infants are functionally and phenotypically dissimilar from those of adults." Comment: CD4 cells, sometimes called T-cells, are a type of white blood cell called a lymphocyte. There are two main types of T-cells. T-4 cells, also called CD4, are “helper” cells. They lead the attack against infections. T-8 cells (CD8) are “suppressor” cells that end the immune response. CD8 cells can also be “killer” cells that kill cancer cells and cells infected with a virus. DTaP shots are creating immune system CD4 cells that are different than the CD4 cells seen in adults. Is this good? Bad? Cancer causing? The abstract of this article doesn’t explain the details.

May 2, 2012 - Reports Highlight New Cause of Pertussis, Tickborne Illness, and Better Food Safety "Previously, isolated reports of B holmesii infection in patients with whooping cough–type symptoms had been described. But the data from the Ohio outbreak are the first to assess the incidence of B holmesii infections in a whooping cough outbreak, explained Loren Rodgers, PhD, an officer with the CDC's Epidemic Intelligence Service, who presented the data. In that outbreak, which affected about 900 individuals, testing confirmed that although most cases were caused by B pertussis, about a third were linked to B holmesii, and a few individuals were infected with both microbes." Comment: Bordetella pertussis is one of 9 species of Bordetella bacteria that have been isolated. A previously unrecognized bacterial pathogens, Bordetella holmesii (B. holmesii) was first isolated in 1983; the initial manuscript naming the new bacterial species was published in 1995. B. holmesii has been associated with bacteremia (blood infection), endocarditis (heart muscle infection), and respiratory illness in humans. Pertussis vaccines changing the DNA of the bacteria and new strains are filling the biological niche, causing disease.

May 1, 2012 - Why Do Pertussis Vaccines Fail? "The first reason, and perhaps the most important one, is that our estimates of vaccine efficacy have been inflated because of case definition. Comment: Case definition means the standard by which an illness is confirmed. The WHO’s primary case definition for pertussis requires laboratory confirmation [usually a nasal swab] and at least 21 days of paroxysmal cough. This article contends that without laboratory confirmation or 21 days of cough, it is presumed that the pertussis vaccine has prevented pertussis, which my not be accurate.

April 12, 2012 - Temporal Trends in Bordetella pertussis Populations, Denmark, 1949–2010 "The observed genetic changes of B. pertussis could therefore be related to the introduction of vaccines."

March 15, 2012 - Unexpectedly Limited Durability of Immunity Following Acellular Pertussis Vaccination in Pre-Adolescents in a North American Outbreak "Our data suggests that the current schedule of acellular pertussis vaccine doses is insufficient to prevent outbreaks of pertussis. We noted a markedly increased rate of disease from age 8 through 12, proportionate to the interval since the last scheduled vaccine. Stable rates of testing ruled out selection bias. The possibility of earlier or more numerous booster doses of acellular pertussis vaccine either as part of routine immunization or for outbreak control should be entertained."

March 14, 2012 - Two Closely Related Strains Associated with Pertussis Resurgence in Israel "Eighty-two isolates of Bordetella pertussis analyzed by pulsed-field gel electrophoresis from the epidemic years, 2007-2008, revealed 4 strains with two closely related isolates accounting for 95% of the circulating strains. The most common Israeli strain has the same PFGE cluster as the dominant European BpSR11 strain (PFGE cluster IV[beta]) identified in the 1999-2004 EUpertstrain II project."

March 1, 2012 - Gene Polymorphism in Toll-like Receptor 4: Effect on Antibody Production and Persistence After Acellular Pertussis Vaccination During Adolescence "The fold increase in antibodies to pertussis toxin after original vaccination 10 years ago was significantly lower in subjects with TLR4 polymorphism than in those without (55% vs 86%; P = .028)."

March 1, 2012 - Injection Site and Risk of Medically Attended Local Reactions to Acellular Pertussis Vaccine (full text) "We conducted a retrospective cohort study of children aged 4 through 6 years in the Vaccine Safety Datalink population who received a DTaP vaccination during the period from 2002 through 2006. Medically attended local reactions to the DTaP vaccine were presumptively identified from administrative data and were confirmed by medical record review."

February 2012 - Aerosolized Vaccine as an Unexpected Source of False-Positive Bordetella pertussis PCR Results "Investigation revealed that Pentacel and Adacel vaccines contain high copy numbers of pertussis DNA, which can be aerosolized, causing false-positive pertussis results with PCR testing." [Pentacel vaccine is five-vaccines given in one shot: DTaP, polio (IPV) and Hib vaccine. Adacel (diphtheria, tetanus, and pertussis) is given to people who are at least 10 years old.]

February 2012 - Safety and Immunogenicity of 2 Mixed Primary Infant Immunization Schedules of Pentacel at 2, 4, and 6 Months of Age: A Randomized Controlled Trial Two different pentavalent infant vaccines (five vaccines in one shot) that contain either 5 or 3 component acellular pertussis antigens are authorized in Canada. By mixing the two different vaccines at 2-, 4-, 6-month, the two vaccines produced different antibody reactions."'''[A convenient way to keep vaccine reactions random and inconsistent is to have several versions of the same vaccine with different ingredients and different responses.]

January 16, 2012- Pertussis Pseudo-outbreak Linked to Specimens Contaminated by Bordetella pertussis DNA From Clinic Surfaces "Between November 28, 2008, and September 4, 2009, 125 cases of pertussis were reported, of which 92 (74%) were confirmed positive by PCR testing. Cases occurring after April 2009 (n = 79; 63%) had fewer classic pertussis symptoms (63% vs 98%; P < .01), smaller amounts of B pertussis DNA when tested (mean PCR cycle threshold value: 40.9 vs 33.1; P < .01), and a greater proportion of PCR-positive results (34% vs 6%; P < .01). Cultures and serology for B pertussis were negative. Other common respiratory pathogens were detected. We identified factors that likely resulted in specimen contamination at the point of collection: B pertussis DNA present in clinics from vaccine, clinic standard specimen collection practices, use of liquid transport medium, and lack of clinically relevant PCR cutoffs." [This means that pertussis DNA found in vaccines can contaminate specimens being collected for testing. This could increase the incidence of "reported pertussis" when in fact, it is simply pertussis from the vaccine.]

July 2011 - Anaphylaxis to diphtheria, tetanus, and pertussis vaccines among children with cow’s milk allergy (full text) "We suspect that small injected doses -- similar to the amount of venom from an insect that can induce anaphylaxis -- can trigger reactions in sensitive patients because digestion is by-passed. Most children with cow’s milk allergy receive these vaccines without incident, but the patients we identified have very severe milk allergy, very high milk-specific IgE levels, and past reactions to trace milk contamination. These children tolerated their initial vaccinations but reacted to booster doses." Comment: Bordetella pertussis bacteria {B.pertussis} are grown in a casein-based medium prior to being harvested and processed for use in DTaP vaccines. This study documents 'taht' children with severe cow's milk allergy can be sensitized during the first DTaP shot and have a severe reaction to subsequent vaccinations.

January 11, 2012 - Short-lived immunity against pertussis, age-specific routes of transmission, and the utility of a teenage booster vaccine (full text) "Immunity induced by the acellular pertussis vaccine prevents both disease and transmission, but is short-lived and heterogeneous. The age-mixing patterns lead to little contact between teenagers and infants. Therefore, while a teenage booster vaccine campaign would likely provide strong protection for cohorts of teenagers, it would provide little protection for infants." Comment: Adacel and Boostrix are the new pertussis vaccines targeting teenagers. The push to re-vaccinate teens is supposed to protect infants who are less than 8-weeks of age and have not yet been vaccinated by the DTaP. This study shows that vaccinating teens does little to protect infants from getting pertussis.

January 2012- Assessment of a Mandatory Tetanus, Diphtheria, and Pertussis Vaccination Requirement on Vaccine Uptake over Time "Beginning in April 2006, current employees were offered the Tdap vaccine. HCP [healthcare personnel] were informed of the requirements for vaccination via an employee newsletter and their supervisors, and they were given two years to become compliant with the policy."..."In March 2010, current employees were reminded via an employee newsletter that immunity to pertussis was required of all UNC [University of North Carolina] employees. In September 2010, after an internal review of the policy, current HCP were informed (via supervisors and an employee newsletter)that any persons not providing evidence of a medical contraindication or proof of immunization by November 2, 2010, would be furloughed without pay."Comment: It's a slippery slope to require a shot, which can cause permanent injury and/or illness, in exchange for employment.

January 2012 - Pertussis: What the Pediatric Infectious Disease Specialist Should Know "Control of pertussis by acellular vaccines is possible to some extent if immunization coverage is high and booster doses are given lifelong. However new vaccines with higher efficacy rates are warranted."

December 2011 - Myriad causes contributed to California pertussis outbreak "A late-breaker presentation by Kaiser Permanente researcher Roger P. Baxter, MD, and colleagues concluded that “acellular vaccines appeared to provide less protection than the whole-cell vaccines they replaced, and their effectiveness may wane substantially over time. “The efficacy of the fifth dose of DTaP wanes by more than 40% per year,” Baxter told Infectious Diseases in Children."

October 21, 2011 - 764. Rapid Rise of Incidence Rates of Pertussis in the Five Years Following Complete DTaP Vaccination: Is Immunity Waning Earlier than Expected? "Incidence rates of pertussis increase in magnitude over the five years following completion of the five-dose DTaP series, suggesting waning immunity 3-5 years after the completion of the DTaP series. An evaluation of age at receipt of 5th DTaP dose as well as other factors such as differences in vaccine antigen content will inform our understanding of waning immunity prior to Tdap vaccination."

August 2011- Bordetella pertussis and Concomitant Viral Respiratory Tract Infections Are Rare in Children With Cough Illness "B. pertussis and B. parapertussis infections were rare in patients with cough illness and so were concomitant virus/Bordetella infections. We propose that virus Bordetella coinfections primarily occur by chance."

March 21, 2011 - Natural immune boosting in pertussis dynamics and the potential for long-term vaccine failure (full text) "Serological surveys suggest that people who are reexposed to B. pertussis can exhibit boosting of antibody titers, without developing clinical symptoms. In addition, studies on vaccine efficacy have shown that the pertussis booster vaccine (Adacel) elicits a significantly stronger immune response than the primary vaccine (Daptacel) despite containing five times less pertussis toxin."..."Third, pertussis reemergence in areas with good vaccine policy, such as Massachusetts, is predicted to have been caused by the crossing of a threshold in vaccine coverage, above which the force of infection is low most of the time, resulting in low boosting rates and relatively rapid loss of immunity, thus giving rise to recurrent epidemic outbreaks. Fourth, this model suggests the existence and periodicity of epidemic pertussis outbreaks may be critically shaped by loss and boosting of immunity."

January 14, 2011- Updated Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis (Tdap) Vaccine from the Advisory Committee on Immunization Practices, 2010 These additional recommendations are intended to remove identified barriers and programmatic gaps that contribute to suboptimal vaccination coverage. An important barrier that limited vaccination of persons with Tdap was unknown history of Td booster. Programmatic gaps included lack of a licensed Tdap vaccine for children aged 7 through 10 years and adults aged 65 years and older. In light of the recent increase of pertussis in the United States, the additional recommendations are made to facilitate use of Tdap to reduce the burden of disease and risk for transmission to infants.

September 2010 - Insight into Evolution of Bordetella pertussis from Comparative Genomic Analysis: Evidence of Vaccine-Driven Selection (pdf) "The genome-wide SNPs were used to classify a collection of 316 isolates from five countries. They were differentiated into 42 SPs, most of which grouped into six clusters. The emergence and increase in prevalence of clusters I and IV in Australia, with different APs, provided new and important evidence of selection pressure from vaccination on the evolution of B. pertussis. Cluster I has been identified as a major clone with a worldwide distribution. Most strains of B. pertussis currently causing clinical pertussis have apparently descended from a single prevaccine lineage."

August 2010 - Pearl Kendrick, Grace Eldering, and the Pertussis Vaccine "Although the American medical community readily adopted Kendrick and Eldering’s whooping cough vaccine, the editor of the British Medical Journal expressed more skepticism, arguing that none of the American studies used proper control groups and that their own trials had shown such vaccines to be ineffective."

July 2010 - Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis. (full text) "Some aP vaccine efficacy studies report a significantly higher proportion of B. parapertussis relative to B. pertussis in aP-vaccinated compared with unvaccinated individuals (Bergfors et al. 1999; Liese et al. 2003). These data are consistent with the hypothesis that B. parapertussis gains a selective advantage under aP vaccination. We can envisage at least three possible mechanisms by which aP vaccination could generate this selective advantage, all of which are based on the observation that aP vaccination confers less protection against B. parapertussis than the immunity induced by natural B. pertussis infection or wP vaccination."

June 2010 - Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study "We identified a peak in the number of patients who had seizure onset within 2 days after vaccination. Thus, patients who had seizure onset on the day of or the day after vaccination  were included in the vaccination-proximate group and those who had seizure onset 2 days or more after vaccination or before vaccination were included in the vaccination-distant group. Mean age at seizure onset was weeks  in the vaccination-proximate group and 26·2 weeks in the vaccination-distant group (difference 7·8 weeks, 95% CI).

May 2010 - Pertussis toxin and adenylate cyclase toxin: key virulence factors of Bordetella pertussis and cell biology tools "In 5–10 years, we will have a more complete understanding of the range of effects on the immune response and how specific activities of the toxins contribute to these effects. ... "However, an important question yet to be addressed is whether the activities of PT and ACT, particularly in regard to their effects on immune responses, also promote disease pathogenesis associated with pertussis. Human volunteer studies for pertussis are unlikely to be approved in the near future.

May 2010 - Synergic effect of genotype changes in pertussis toxin and pertactin on adaptation to an acellular pertussis vaccine in the murine intranasal challenge model. (full text) "National surveillance data show that increases in pertussis cases have occurred among all age groups except children less than 1 year old. The most remarkable increase has occurred among adults (individuals ≥20 years old); however, a significant increase even in the vaccinated 1- to 9-year-old"

March 3, 2010 - Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis "Further, we show that aP vaccination impedes host immunity against B. parapertussis—measured as reduced lung inflammatory and neutrophil responses. Thus, we conclude that aP vaccination interferes with the optimal clearance of B. parapertussis and enhances the performance of this pathogen.

February 2010 - Pertussis antibodies in postpartum women and their newborns (pdf) "Infants born to mothers that had a previous pertussis infection had more potentially protective antibodies at 6 weeks than those born to mothers 'who did not have a previous pertussis infection."..."Conclusion: Approx. 75% of infants were born with pertussis antibodies lower than the levels associated with 'potential' protection. Nearly 90% of infants were predicted to have little antibodies by 6 weeks. "Conclusion: Approx. 75% of infants were born with pertussis antibodies lower than the levels associated with POTENTIAL protection. Nearly 90% of infants were predicted to have little antibodies by 6 weeks.

December 29, 2009 - Production and characterization of recombinant pertactin, fimbriae 2 and fimbriae 3 from Bordetella pertussis (pdf) "So far there have been no separate purified Fim2 and Fim3 available. In addition, antigenic divergence between vaccine strains and clinical isolates as well as the possible presence of other reactogenic contaminants, should be considered during purification of those proteins."..."As the difference occurred between B. pertussis vaccine strains and circulating isolates in many countries , it has been proposed that the strain variation may have effect on the vaccine efficacy.

October 30, 2009 - Estimating the Duration of Pertussis Immunity Using Epidemiological Signatures "Our analyses found that a range of durations of naturally acquired immunity is consistent with the pre-vaccine and vaccine era data. If repeat infections are as infectious as primary infections with no immune-boosting then this range is 60–100 years, if they are half as infectious or 50% lead to immune-boosting infections, then this range is 30–80 years. These values are robust to changes in primary-repeat contact rates and variation in the reporting rate of repeat infections."

February 2008 - What is new in pertussis? (full text) These vaccines differ both in terms of their active ingredients and in terms of the other diseases for which coverage is provided (e.g., polio, diptheria). For example, Repevax (Sanofi Pasteur) contains diptheria, tetanus, pertussis (acellular, component) as well as inactivated polio, whereas ADACEL contains only tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.

January 2008 - Real-Time Polymerase Chain Reaction Detection of Bordetella pertussis DNA in Acellular Pertussis Vaccines "2 of 5 acellular pertussis vaccines were found to contain B. pertussis DNA. Because residual DNA in vaccines can cause environmental contamination, the administration of acellular pertussis vaccines to patients should be physically separated from the collection of patients' specimens for testing of B. pertussis DNA by real-time PCR."

2007 - WHO Recommendations for whole-cell pertussis vaccine (pdf) "The role of different toxins, such as pertussis toxin, heat labile (dermonecrotic) toxin, tracheal cytotoxin, adenylate cyclase toxin and endotoxin in immunity to the natural infection or in immunization is not fully understood. A potential link between the presence of some of these toxins and reactogenicity in humans has been reported, but the mechanisms of their action and the contribution of individual toxins to overall toxicity remains unclear.

2007 - Neurological morbidity and the pertussis vaccine: An old story revisited " We describe 3 children with neurological disorders that developed in association with their receipt of the whole-cell pertussis vaccine. Newer studies supported the ability of the wP vaccine to adversely affect the CNS. The possibility that it worsened their clinical course in infancy by causing additional damage should not be disregarded."

March 16-17, 2006 - WHO Working Group on standardization and control of acellular pertussis vaccines (pdf) "Two years later, the consultation held in March 2005 considered clinical assessment of new acellular pertussis vaccines and identified difficulties in their licensing. The latter is due to the lack of correlates of protection, on the one hand, and the complexity of comparison between new vaccines and those tested in efficacy trials conducted in the 1980s and 1990s on the other hand."

June 19, 2006 - Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants (full text) "There is an increase in adverse cardiorespiratory events following the first dose of DTP-IPV-Hib in preterm infants. Lower current weight was identified as a risk factor, with the risk being equivalent for whole cell versus acellular pertussis vaccine."

April 24, 2006 - Differences of circulating Bordetella pertussis population in Argentina from the strain used in vaccine production "Many reports suggest that the decline of vaccine efficacy due to antigenic shifts in the circulating Bordetella pertussis might be among the factors that contribute to pertussis re-emergence in different parts of the world."..."The presence of this Bordetella species together with the observed differences between circulating B. pertussis and the strain used in vaccine production should be considered for the development of an improved vaccine."

December 2005 - Th2-Associated Local Reactions to the Acellular Diphtheria-Tetanus-Pertussis Vaccine in 4- to 6-Year-Old Children "if the DTaP booster is accompanied by concomitant IPV boosting at the same site, ensuing Th2-associated local reactions and the accompanying boosting of TT-specific IgE are significantly reduced, while IgG boosting improves. This suggests the possibility that reactivation of Th1-polarized poliovirus-specific memory cells by IPV may provide “bystander” feedback inhibition of the Th2 component of DTaP-specific memory, both locally and in the draining lymph node. This possibility merits more-detailed investigation employing larger study groups, including subjects primed during infancy with IPV, which is now used in many countries in preference to oral poliovirus vaccine."

June 30, 2005 - Importance of the Degree of Antigen Polymerization by Detoxification in Modulating the Immunogenicity of Acellular Pertussis Vaccine (full text) "The detoxification of acellular pertussis bulks by formaldehyde and lysine induced some biophysical and biochemical modifications of antigens constituting acellular pertussis vaccines, including their polymerization and also notable rise in pertactin content after the filtration of final detoxified bulks. These modifications also led to changes in immunogenicity of the acellular pertussis vaccines and the detailed investigation revealed that the polymerization of antigens and its degree are the major factors for any significant increase in immunogenicity. In addition, the vaccines from highly-polymerized antigens exhibited a typical dose-response pattern and the dose of detoxified bulk for the optimal immunogenicity was around 8 µg PN/mL."

December 2004 - Acellular Pertussis Vaccines and Complement Killing of Bordetella pertussis "Despite high vaccination rates, the number of reported cases of pertussis in the United States has increased steadily since the 1980s (22). Developing a pertussis vaccine with a greater potential to elicit bactericidal activity could reduce bacterial carriage and reduce the incidence of disease."

May 2004 - Efficacies of whole cell and acellular pertussis vaccines against Bordetella parapertussis in a mouse model. "Although, the acellular vaccines conferred some protection against B. parapertussis early in infection, the values were not significant. Later in infection, a highly significant enhancement of colonisation by B. parapertussis was observed in mice vaccinated with acellular vaccines. The whole cell vaccines protected significantly better than the acellular vaccines against B. parapertussis. The possible consequences of a switch from whole cell to acellular vaccines was discussed in the light of our findings."

February 24, 2004 - Acellular pertussis vaccines and methods of preparation thereof (patent) Aventis Pastuer Limited (Toronto, CA) "PT is detoxified to remove undesired activities which could cause side reactions of the final vaccine. Any of a variety of conventional chemical detoxification methods can be used, such as treatment with formaldehyde, hydrogen peroxide, tezranitro-methane, or glutaraldehyde.

February 2004 - Toxicity and potency evaluation of pertussis vaccines. (pdf) "Despite the successful implementation of immunization with acellular pertussis vacines of different compositions, basic problems remain in their standardization. These vaccines were introduced against a background of a variety of formulations with no agreed standard and with no satisfactory animal model for the establishment of potency. This was a consequence of incomplete information on the nature of vaccine induced protective immunity and lack of immune correlates of protection."

August 15, 2003 - Bordetella pertussis Protein Pertactin Induces Type-Specific Antibodies: One Possible Explanation for the Emergence of Antigenic Variants? (pdf) "The antibodies to Prn1 play a role in protection against pertussis but may not be decisive when the level of antibodies to other antigens (e.g., PT) is high."

August 11, 2003 - Efficacies of whole cell and acellular pertussis vaccines against Bordetella parapertussis in a mouse model "The whole cell vaccines protected significantly better than the acellular vaccines against B. parapertussis. The possible consequences of a switch from whole cell to acellular vaccines was discussed in the light of our findings."

April 2003 - Diphtheria, Tetanus and Acellular Pertussis Vaccine (DTaP): A Case Study (pdf) "But reliable data on the most rare events those that were most controversial were not available from the pre-licensure trials, primarily because a much larger pool of subjects was required."..."(from an all DTP to an all-DTaP vaccine schedule for infants and children) took place incrementally, over a 10-year period."

January 2003 - Pertussis resurgence in Canada largely caused by a cohort effect. "The sudden increase in pertussis incidence in Canada can be largely attributed to a cohort effect resulting from a poorly protective pertussis vaccine used between 1985 and 1998."

September 27, 2002 - Structural Basis for Gluten Intolerance in Celiac Sprue "The primary sequence of the 33-mer gliadin peptide also had homologs 'among a few nongluten proteins. Among the strongest homologs were internal sequences from pertactin (a highly immunogenic protein from Bordetella pertussis) and a mammalian protein tyrosine phosphatase of unknown function. In both cases, available information suggested that this homology could have biological relevance. For example, the region of pertactin that is homologous to the 33-mer gliadin peptide is known to be part of the immunodominant segment of the protein.

July-September 2002 - Serious neurological conditions following pertussis immunization: an analysis of endotoxin levels, the vaccine adverse events reporting system (VAERS) database and literature review "The results indicated that whole-cell DTP vaccine contained high levels of endotoxin and was statistically significantly more reactogenic than acellular DTaP vaccine. The presence of bias in the VAERS database was not borne-out. The recommendation by the American Academy of Paediatrics to use acellular DTaP vaccine for the entire childhood vaccination schedule beginning in 1996 and the absence of the availability of whole-cell DTP in the US beginning in 2001 seems well justified based upon the results of this study."

July 2002 - The True Story of Pertussis Vaccination: A Sordid Legacy? (pdf) ""In 1961, Dr. C. N. Christensen, a physician from Eli Lilly and company, Then a whole-cell pertussis producer, was commissioned to study whether the mouse toxicity test had been serving its purpose. The results of his study were conveyed to all manufacturers of whole-cell pertussis vaccine and were presented at the 1963 International Symposium on Pertussis. He concluded: "It is obvious that severe neurologic reactions have occurred in children after immunization with pertussis vaccines which have passed the toxicity and potency tests currently in use''' ... It was clear that there was no correlation between the mouse toxicity test and the reaction rates in children."

December 2001 - Polymorphism of Bordetella pertussisIsolates Circulating for the Last 10 Years in France, Where a Single Effective Whole-Cell Vaccine Has Been Used for More than 30 Years (full text) "Polymorphism of B. pertussis has been described by bacteriologists but not seriously taken into consideration. Indeed, bacteriologists have argued that it would be better to change vaccine strains regularly to coincide with isolates circulating in the susceptible population."

November 2001 - Role of the polymorphic region 1 of the Bordetella pertussis protein pertactin in immunity (full text) "An important, unresolved, question is whether, and to what extent, variation in pertactin affects the efficacy of acellular vaccines. In addition to pertactin, acellular vaccines contain filamentous haemagglutinin, fimbriae and pertussis toxin, which are also involved in protection against pertussis. Possibly, the presence of high concentrations of multiple antigens may minimize the effect of variation in pertactin."

June 2001 - Adaptation of Bordetella pertussis to Vaccination: A Cause for Its Reemergence? (pdf) "However, nonvaccine types of pertactin and PtxS1 gradually replaced the vaccine types in later years and were found in 90% of strains collected from 1990 to 1996. These results suggest that vaccination has caused strains that are antigenically distinct from vaccine strains to be selected."

December 2000 - Characterization of Bactericidal Immune Responses following Vaccination with Acellular Pertussis Vaccines in Adults "In summary, booster immunization of adults with acellular pertussis vaccines 'was not found to increase bactericidal activity over preimmunization levels'''. Identifying ways to promote bactericidal immune responses might improve the efficacy of acellular pertussis vaccines."

November 2000 - Polymorphism in Bordetella pertussis Pertactin and Pertussis Toxin Virulence Factors in the United States, 1935–1999 (full text) "This program serves as a significant source of prospective isolates and related clinical and epidemiologic information for monitoring the B. pertussis population structure for the impact of epidemiologically relevant changes in vaccination coverage, type of vaccine used, severity of the disease, and trends in the disease incidence."

October 2000 - Pertussis Infection in Fully Vaccinated Children in Day-Care Centers, Israel (full text) "Vaccinated adolescents and adults may serve as reservoirs for silent infection and become potential transmitters to unprotected infants. The whole-cell vaccine for pertussis is protective only against clinical disease, not against infection. Therefore, even young, recently vaccinated children may serve as reservoirs and potential transmitters of infection."

July-August 2000 - Reemergence of Pertussis in the Highly Vaccinated Population of the Netherlands: Observations on Surveillance Data (pdf) "The remarkable increase in reported cases among vaccinated patients over a wide age range, starting 2 years before the 1996 outbreak, suggests a mismatch between circulating strains and vaccine strains. Antigenic divergence between vaccine strains and clinical isolates was observed for two important protective antigens, pertactin and pertussis toxin."

November 1999 - Local reactions and IgE antibodies to pertussis toxin after acellular diphtheria-tetanus-pertussis immunization. (pdf)"The higher median pre- and post-booster levels of pertussis toxin specific immunoglobulin E and post-booster levels of IgG to pertactin and diphtheria in children with local side-effects reflect a multifactorial immunological mechanism of such reactions."

September 1999 - Vaccination with Pertussis Toxin Alters the Antibody Response to Simultaneous Respiratory Syncytial Virus Challenge "Although similar antibody titers to pertussis antigens were detected whether the DTP vaccine was administered with or separately from the Hib and IPV proteins, coadministration of DTP appeared to depress the subsequent antibody response to both Hib and IPV. One possible explanation suggested by the experiments described here is that DTP might suppress IFN-γ—mediated antibody responses to the coadministered antigens while leaving the IL-4—induced response intact."

August 1999 - Antigenic variants in Bordetella pertussis strains isolated from vaccinated and unvaccinated children - (pdf) "The recent literature (Andrews et al., 1997; Bass & Wittler, 1994; de Melker et al., 1997; De Serres et al., 1995) has documented the increase in the incidence of pertussis in highly vaccinated populations, and this has led to the hypothesis that B. pertussis strains have evolved which are less affected by vaccine-induced immunity."

July 1999 - Pertussis adjuvant prolongs intestinal hypersensitivity - "Conclusions: Our findings indicate nanogram quantities of PT, when administered with a food protein, result in long–term sensitization to the antigen, and altered intestinal neuroimmune function. These data suggest that exposure to bacterial pathogens may prolong the normally transient immune responsiveness to inert food antigens."

November 1998 - Report of a US public health service workshop on hypotonic-hyporesponsive episode (HHE) after pertussis immunization. "Numerous studies of adverse events after pertussis vaccination during the last several decades have described events categorized as HHE, “shock,”collapse,” “anaphylaxis /collapse, episodes of pallor or cyanosis,” and so forth. Although many of these studies' categories had clinical features in common, the studies usually did not define the categories, and it is likely that inclusion criteria varied. Indeed, there has been no generally accepted definition of HHE, and a standardized definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components."

November 1998 - Early childhood infection and atopic disorder. "Interpretation of the prediction of atopic disorders by immunisation with whole-cell pertussis vaccine and treatment with oral antibiotics needs to be very cautious because of the possibilities of confounding effects and reverse causation. However, plausible immune mechanisms are identifiable for the promotion of atopic disorders by both factors and further investigation of these associations is warranted."

February 1998 - Polymorphism in the Bordetella pertussisVirulence Factors P.69/Pertactin and Pertussis Toxin in The Netherlands: Temporal Trends and Evidence for Vaccine-Driven Evolution (full text) "There is evidence that the incidence of pertussis is increasing in populations vaccinated with WCVs and our results suggest that one of the factors which has contributed to this phenomenon may be the decline of vaccine efficacy due to antigenic shifts in the B. pertussis population. Our findings also may have implications for the efficacy of ACVs, many of which contain both P.69 and pertussis toxin.

November 1997 - Randomised controlled trial of two-component, three-component, and five-component acellular pertussis vaccines compared with whole-cell pertussis vaccine "Serious adverse events occurred in 182 children within 6 months of vaccination, including 30 deaths. All but one of these babies had received simultaneous vaccination with inactivated polio vaccine and tetanus-conjugate H influenzae type b vaccine. 39 serious adverse events occurred in the two-component vaccine group, 36 in the three-component-vaccine group, 47 in the five-component-vaccine group, and 60 in the whole-cell-vaccine group. The number of events did not differ significantly between groups (p=0.06). 103 children had serious adverse events within 3 days of vaccination. 101 of these were transient hypotonic hyporesponsiveness episodes, of which 87 occurred after the first dose, 13 after the second dose, and one after the third dose. 33 of these children were admitted to hospital. 22 hypotonic hyporesponsiveness episodes occurred in the two component-vaccine group, 16 among recipients of three-component-vaccine group, 29 in the five component-vaccine group and 34 in the whole-cell vaccine group (0-06). Relative risks, with whole-cell vaccine group as the reference, were 0.65"..."The efficacy of acellular vaccines depends on the number of components, and different whole-cell vaccines have variable efficacies."

March 28, 1997 - Pertussis Vaccination: Use of Acellular Pertussis Vaccines Among Infants and Young Children (pdf) "More severe systemic events (e.g., convulsions [with or without fever] and hypotonic hyporesponsive episodes) occur less frequently (ratio of one case to 1,750 doses administered) among children who receive whole-cell DTP vaccine (5 ). Acute encephalopathy occurs even more rarely (ratio of 0–10.5 cases to one million doses administered) (7 ). Experts disagree on whether whole-cell pertussis vaccine causes lasting brain damage, but agree that if the vaccine causes such damage it does so only rarely (7 ). Concerns about safety prompted the development of more purified (acellular) pertussis vaccines that are associated with a lower frequency of adverse events and are effective in preventing pertussis disease."

1997 - Are serological responses to acellular pertussis antigens sufficient criteria to ensure that new combination vaccines are effective for prevention of disease? "Thus, although diphtheria-tetanus-acellular pertussis (DTaP) vaccine has been considered a prime building block in the development of new combination vaccines, modifying DTaP by the addition of new vaccine components may decrease the ability of the vaccine to protect against pertussis without a change in serum antibody response."

November 1991 - Differences in antibody response to whole-cell pertussis vaccines. "Evaluation of other comparative data sets that were available provided further support for the conclusion that the two commercially available WCVs consistently differed in their ability to induce antibody to pertussis toxin. These findings have important implications for the design and interpretation of clinical trials comparing acellular and WCV products."

1991 - Adverse Effects of Pertussis and Rubella Vaccines The National Academies Press. Comment: This is a long explanation for the number of adverse effects caused by the pertussis and rubella vaccines.

November 26, 1990 - United States Court of Appeals, Sixth Circuit. Melanie Sue ACKLEY, by next friend Tami Sue Ackley, Plaintiffs-Appellants, v. WYETH LABORATORIES, INC., and Wyeth Laboratories Division of American Home Products Corporation, Defendants-Appellees, Prentice Hall Corporation System; Sooja Kim, M.D.; Madison Pediatrics, Inc., Defendants. "Wyeth documents showing that it had knowledge of the higher risk of its whole cell design since the mid 1970s. (J.A. 326, 331, 350, 353). These consist of: (1) a 1977 letter from Dr. M.Z. Bierly of Wyeth, stating that "we would assume" that whole cell vaccines would have a higher incidence of "systemic (febrile) responses and perhaps local reactions" than Tri-Solgen; a 1976 Wyeth finance committee memo stating that Tri-Solgen is "less reactive" than other vaccines and that the Tri-Solgen design is "superior to any others on the market, including Wyeth's"; a 1980 Wyeth summary of a meeting with members of the FDA's Bureau of Biologics (BuBio) stating that in the Bureau's opinion, whole cell design is efficacious but too reactive; and a 1982 Wyeth summary of a BuBio pertussis conference, at which Bureau officials expressed the opinion that the acellular design looked promising in its use in Japan and that techniques for testing and manufacturing it were available."

October 1988 - Infectious episodes following diphtheria-pertussis-tetanus vaccination. A preliminary observation in infants. "In addition to reactive fever during the first 3 days following DPT immunization, an increase in infectious episodes seems to occur in infants during the month following administration of this vaccine."

March-April 1992 - Acellular versus whole-cell pertussis vaccines "Projected to the 400,000 children across Canada who receive this vaccine annually prior to school entry implies that over 30,000 have arms temporarily immobilized by pain. Fortunately, local symptoms resolve within a few days and are not usually accompanied by systemic adverse effects. The cause likely rests with changes made to the vaccine when alum-containing products were introduced after 1980. High diphtheria toxoid content has been identified as a contributor to vaccine reactions but other constituents such as pertussis vaccine and aluminum phosphate may also be important. Acellular pertussis DT vaccines might offer an early solution. Licensure is pending in the United States for such products to be used for booster doses only; even greater justification for this interim measure might exist in Canada if new vaccines reduce local reactions.

1991 - Possible Involvement of Aluminum Salts in Erythema Multiforme, Encephalopathy, or Other Adverse Events After Pertussis Immunization "Interest has developed recently in the potential health effects of aluminum, particularly in the setting of chronic renal failure, in which aluminum is not excreted from the body normally (Alfrey, 1984; Monteagudo et al., 1989)."

October 1988 - Infectious episodes following diphtheria-pertussis-tetanus vaccination. A preliminary observation in infants. "In addition to reactive fever during the first 3 days following DPT immunization, an increase in infectious episodes seems to occur in infants during the month following administration of this vaccine."

May 16, 1981 - Pertussis immunisation and serious acute neurological illness in children. (pdf) "Of the 35 notified children, 32 had no previous neurological abnormality. A year later two had died, nine had developmental retardation, and 21 were normal. A significance association was shown between serious neurological illness and pertussis vaccine, though cases were few and most children recovered completely."

September 1987 - Murine responses to immunization with pertussis toxin and bovine serum albumin: I. Mortality observed after bovine albumin challenge is due to an anaphylactic reaction.

April 1987 - Anaphylaxis or so-called encephalopathy in mice sensitized to an antigen with the aid of pertussigen (pertussis toxin). "Sensitization of mice with 1 mg of bovine serum albumin (BSA) or chicken egg albumin (EA) given intraperitoneally and 300 to 400 ng of pertussigen (pertussis toxin [Ptx]) given intravenously (i.v.) induced a high degree of anaphylactic sensitivity when the mice were challenged i.v. with 1 mg of antigen 14 days later."

1987 - A model for experimental asthma: provocation in guinea-pigs immunized with Bordetella pertussis "Guinea-pigs were sensitized with killed Bordetella pertussis (3.85 X 10(11) cells . kg-1). The presence of the immediate type of immune response was verified by passive cutaneous anaphylaxis (PCA)."

1985 - Murine model for pertussis vaccine encephalopathy: role of the major histocompatibility complex; antibody to albumin and to Bordetella pertussis and pertussis toxin. "A mouse model for pertussis immunization encephalopathy has been described with features that closely resemble the severe adverse reactions occasionally seen after pertussis vaccine administration, including seizures and a shock-like state leading to death. These reactions are produced with nearly one hundred percent efficiency provided that the mice immunized with Bordetella pertussis have 1) the appropriate major histocompatibility (H-2) genotype, 2) have been sensitized to bovine serum albumin (BSA), and 3) that the injected B. pertussis contained sufficient amounts of pertussis toxin."

May 1983 - The non-specific enhancement of allergy. I. In vivo effects of Bordetella pertussis vaccine on IgE synthesis. "Bordetella pertussis organisms, with or without a small dose of alumhydroxide, enhance in rats the production of IgE antibodies to an unrelated antigen, even if this antigen has been administered 6 weeks beforehand. This non-specific enhancement of IgE antibodies is accompanied by a substantial rise in total serum IgE and by the production of IgE antibodies to B. pertussis."

September 1981 - Biological activities of crystalline pertussigen from Bordetella pertussis "We studied various biological activities of crystalline pertussigen and found that in mice as little as 0.5 ng of pertussigen induced hypersensitivity to histamine, 8 to 40 ng induced leukocytosis, 2 ng increased production of insulin, 0.1 ng increased production of immunoglobulin E and immunoglobulin G1 antibodies to hen egg albumin, 9.5 ng increased susceptibility to anaphylactic shock, and 0.5 ng increased the vascular permeability of striated muscle. We also found that in Lewis rats 20 ng of pertussigen promoted the induction of hyperacute experimental allergic encephalomyelitis."

April 1964 - Local and Systemic Anaphylaxis in the Pertussis-inoculated Mouse "The following experiment indicates that the incidence of active cutaneous anaphylaxis in the pertussis-inoculated mouse 'parallels the incidence of systemic anaphylaxis."

December 1963 - Anaphylactic reactions in mice induced by Bordetella pertussis lipopolysaccharide "The lipopolysaccharides of certain gramnegative organisms similarly possess this capacity to sensitize. Mice pretreated withB. pertussis will show fatal anaphylaxis-like reactions when challenged by the intravenous injection of these lipopolysaccharides".

September 1958 - The altered reactivity of mice after inoculation with Bordetella pertussis vaccine (pdf) "The concomitant sensitivity of the pertussis inoculated mouse to serotonin, histamine, and anaphylaxis can hardly be considered coincidental. It it tempting to postulate that enhanced susceptibility to active and passive anaphylaxis can be explained on the basis of concurrent sensitivity to histamine and serotonin. Active anaphylaxis, howerver, will occur in pertussis inoculated mice at a time when histamine and serotonin sensitivity have declined greatly or have completely disappeared."

July 5, 1958 - Neurological Complications of Pertussis Immunization "Because the fits and associated features persisted, he was admitted to hospital three weeks after the inoculation. Observation revealed a child without interest in anything, who, if placed in a sitting position, could remain thus unsupported for only a few seconds and each bout a few minutes. Apart from these findings, physical examination revealed no abnormalities, and the blood count, cerebrospinal fluid, and urine examinations were normal."..."At 11 months of age the child was severely retarded mentally, and phenobarbitone, 1/4 gr. (16mg.) twice daily, was needed to control his fits."

June 1957 - Sensitivity of Pertussis-Inoculated Mice to Serotonin. "Pertussis vaccine sensitizes mice to the lethal effects of serotonin."

March 21, 1952 - Anaphylactic shock in the pertussis-vaccinated mouse "The possible relationship between the enhancement of experimental anaphylaxis by H. pertussis vaccine and the questionable observation of the production of the clinical syndrome of paralysis following vaccination is discussed."

August 18, 1945 - Vaccination Against Whooping-Cough "When vaccine was given to the infants of mothers who accepted the offer, and the infants of mothers who refused were treated as controls, the results of vaccination were favourable. When, however, the element of selection was eliminated by vaccinating infants in alternate rotation, no difference between the vaccinated and control groups was observed."