Joan Bartlett

Waning Protection after Fifth Dose of Acellular Pertussis Vaccine in Children

BACKGROUND In the United States, children receive five doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine before 7 years of age. The duration of protection after five doses of DTaP is unknown. METHODS We assessed the risk of pertussis in children in California relative to the time since the fifth dose of DTaP from 2006 to 2011. This period included a large outbreak in 2010. We conducted a case-control study involving members of Kaiser Permanente Northern California who were vaccinated with DTaP at 47 to 84 months of age. We compared children with pertussis confirmed by a positive polymerase-chain-reaction (PCR) assay with two sets of controls: those who were PCR-negative for pertussis and closely matched controls from the general population of health-plan members. We used logistic regression to examine the risk of pertussis in relation to the duration of time since the fifth DTaP dose. Children who received whole-cell pertussis vaccine during infancy or who received any pertussis-containing vaccine after their fifth dose of DTaP were excluded. RESULTS We compared 277 children, 4 to 12 years of age, who were PCR-positive for pertussis with 3318 PCR-negative controls and 6086 matched controls. PCR-positive children were more likely to have received the fifth DTaP dose earlier than PCR-negative controls (P<0.001) or matched controls (P=0.005). Comparison with PCR-negative controls yielded an odds ratio of 1.42 (95% confidence interval, 1.21 to 1.66), indicating that after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year. CONCLUSIONS Protection against pertussis waned during the 5 years after the fifth dose of DTaP. (Funded by Kaiser Permanente).

Comparative Effectiveness of Acellular Versus Whole-Cell Pertussis Vaccines in Teenagers

BACKGROUND: During the 1990s, the United States switched from combined diphtheria, tetanus toxoids, whole-cell pertussis (DTwP) vaccines to combined acellular pertussis (DTaP) vaccines because of safety concerns. After a 2010–2011 pertussis outbreak, we sought to evaluate whether disease risk in 10 to 17 year olds differed between those who previously received DTwP from those who received DTaP. METHODS: A case-control study among individuals born from 1994 to 1999 who received 4 pertussis-containing vaccines during the first 2 years of life at Kaiser Permanente Northern California (KPNC). We separately compared pertussis polymerase chain reaction (PCR)-positive cases with PCR-negative and KPNC-matched controls. We assessed risk of pertussis relative to vaccine type in early childhood (4 DTwPs, mixed DTwP/DTaP, or 4 DTaPs) by using conditional logistic regression stratified for calendar time and adjusted for gender, race, medical clinic, and receipt of reduced antigen content acellular pertussis (Tdap) vaccine. RESULTS: 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.

Effectiveness of pertussis vaccines for adolescents and adults: case-control study

Objective To assess the effectiveness of reduced acellular pertussis (Tdap) vaccines in adolescents and adults. Setting Kaiser Permanente Northern California. Design Case-control study. Participants All polymerase chain reaction (PCR) confirmed cases of pertussis in members aged 11 years and older from January 2006 to December 2011. We compared the Tdap vaccination status of PCR positive cases with two control groups: people testing negative for pertussis by PCR and closely matched people from the general Kaiser Permanente Northern California population. Main outcome measure PCR confirmed pertussis. The association of Tdap vaccination with the odds of pertussis infection was estimated by conditional logistic regression, with adjustment for calendar time, pertussis vaccine type received in early childhood, age, sex, race or ethnic group, and medical clinic. We calculated Tdap vaccine effectiveness as 1 minus the adjusted odds ratio. Results The study population included 668 PCR positive cases, 10 098 PCR negative controls, and 21 599 Kaiser Permanente Northern California matched controls. Tdap vaccination rates were 24.0% in PCR positive cases and 31.9% in PCR negative controls (P<0.001). The adjusted estimate of effectiveness of Tdap vaccination against pertussis was 53.0% (95% confidence interval 41.9% to 62.0%) in the comparison with PCR controls, and 64.0% (55.5% to 70.9%) in the comparison with Kaiser Permanente Northern California controls. Conclusion Tdap vaccination was moderately effective at preventing PCR confirmed pertussis among adolescents and adults.

Waning Tdap Effectiveness in Adolescents

BACKGROUND AND OBJECTIVE: Because the effectiveness of diphtheria-tetanus-acellular pertussis (DTaP) vaccine wanes substantially after the fifth dose at ages 4 to 6 years, there is a growing cohort of adolescents who rely on tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) for protection against pertussis. Yet despite high Tdap vaccine coverage among adolescents, California experienced large pertussis outbreaks in 2010 and 2014. We investigated Tdap vaccine effectiveness (VE) and waning within Kaiser Permanente Northern California among adolescents exclusively vaccinated with DTaP vaccines. METHODS: We modeled pertussis risk in relation to Tdap vaccination status among adolescents beginning on their 10th birthday. We estimated the hazard ratio (HR) for each subsequent year after Tdap compared with unvaccinated adolescents by using Cox regression, adjusting for calendar time, age, gender, race, and facility. We calculated VE as 1 − HR. We also treated time since Tdap vaccination as a continuous variable and estimated the change in the HR per 1-year increase since vaccination. RESULTS: 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. Adolescents who were more remote from Tdap were significantly more likely to test positive for pertussis than were those vaccinated more recently (HR per year 1.35, 95% CI 1.22 to 1.50). CONCLUSIONS: 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..

Safety of Zostavax™—A cohort study in a managed care organization

BACKGROUND Zostavax™ is a live, attenuated varicella-zoster virus vaccine indicated for the prevention of herpes zoster (shingles). An observational post-licensure (Phase IV) study was conducted at Kaiser Permanente Northern California (KPNC), a US managed care organization, to assess the safety of zoster vaccine in people 60 years of age or older, vaccinated in routine medical care. METHODS We performed a cohort study, comparing rates of clinical events resulting in hospitalizations or emergency department visits in a 42-day risk time period immediately following vaccination with rates in the same cohort in a subsequent comparison time period. The study data were reviewed and interpreted by an external safety review committee of 3 independent experts. RESULTS Approximately 29,000 people ≥ 60 years of age were vaccinated with zoster vaccine from July 2006 to November 2007. Of the 386 comparisons performed for the main analysis, 4 had an increased relative risk with a nominal p-value ≤ 0.05. After medical records review, the timing of these conditions and procedures was found to be often prior to vaccination, and no clear increase in health events was observed in the risk period following vaccination compared to later. Persons receiving zoster vaccine appeared to be in their optimal health at the time of vaccination, which led to an apparent protective effect of the vaccine for some health outcomes, due to the study design. CONCLUSIONS There was no evidence of a safety concern for zoster vaccine.

A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 5 through 17 years of age

BACKGROUND Live attenuated influenza vaccine (LAIV) was licensed in 2003 in the United States for use in individuals aged 5-49 years. METHODS A prospective observational postmarketing study was conducted to evaluate the safety of LAIV. Rates of medically attended events (MAEs) and serious adverse events (SAEs) in eligible children aged 5-17 years receiving LAIV as part of routine care from October 2003 to March 2008 were compared with rates in nonrandomized self, matched unvaccinated, and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls. All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed. Statistical significance was assigned without multiplicity adjustment. RESULTS 43,702 LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children. Of approximately 9500 MAE incidence rate comparisons, 204 were statistically significantly higher and 168 were statistically significantly lower in LAIV recipients versus controls. No pattern of MAE rate differences suggested a safety signal with LAIV. Asthma/wheezing MAEs were not statistically increased in LAIV recipients. No anaphylaxis events occurred within 3 days postvaccination. Rates of SAEs were similar between LAIV and control groups. Two SAEs were considered possibly related to LAIV: Bells palsy and nonspecific paroxysmal spell. CONCLUSIONS Results of this postlicensure evaluation of LAIV safety in US children aged 5-17 years are consistent with preapproval clinical studies and Vaccine Adverse Event Reporting System reports, both of which demonstrated no significant increase in asthma/wheezing events or other adverse outcomes among eligible children who received LAIV.

A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in adults 18–49 years of age

BACKGROUND The Ann Arbor strain-live attenuated influenza vaccine (LAIV) was licensed in 2003 for use in the United States for individuals aged 5-49 years of age. As part of a postmarketing commitment to safety, LAIV was studied in adults 18-49 years participating in the Kaiser Permanente Health Plan over 5 influenza seasons. METHODS Individuals received LAIV as part of routine care from October 2003 through March 2008. Using Kaiser Permanente databases, rates of medically attended events (MAEs) and serious adverse events (SAEs) in LAIV recipients were compared with rates in multiple non-randomized control groups which included a self-control group, matched unvaccinated controls, and matched controls vaccinated with inactivated influenza vaccine (TIV). RESULTS A total of 21,340, 18,316, and 21,340 subjects received LAIV, TIV and no vaccine, respectively. More than 5500 MAE incidence rate comparisons were performed, and of these, 257 (5%) yielded statistically significant differences with 72 and 185 occurring at a higher and lower rate after LAIV compared with control groups, respectively. The pattern of MAE rate differences did not suggest any safety signal associated with LAIV. There were 47 SAEs noted, and no individual SAE occurred at a significantly higher or lower rate in LAIV recipients relative to control groups in any comparison. Only 2 SAEs (migraine/sinusitis and Bells palsy) were considered possibly or probably related to LAIV. CONCLUSION The results of this post-licensure evaluation of LAIV safety in individuals 18-49 years of age are consistent with pre- and post-approval clinical studies as well as reports to the U.S. Vaccine Adverse Events Reporting System, all of which demonstrated no significant adverse outcomes among eligible individuals following receipt of LAIV.

Long-Term Effectiveness of the Live Zoster Vaccine in Preventing Shingles: A Cohort Study

Abstract A live attenuated zoster vaccine was licensed in the United States in 2006 for prevention of shingles in persons aged 60 years or older; the indication was extended in 2011 to cover those aged 50–59 years. We assessed vaccine effectiveness (VE) against shingles for 8 years after immunization at Kaiser Permanente Northern California. VE was estimated by Cox regression with a calendar timeline that was stratified by birth year. We adjusted for demographics and time-varying covariates, including comorbidities and immune compromise. From 2007 to 2014, 1.4 million people entered the study when they became age eligible for vaccination; 392,677 (29%) received the zoster vaccine. During 5.8 million person-years of follow-up, 48,889 cases of shingles were observed, including 5,766 among vaccinees. VE was 49.1% (95% confidence interval (CI): 47.5, 50.6) across all follow-up. VE was 67.5% (95% CI: 65.4, 69.5) during the first year after vaccination, waned to 47.2% (95% CI: 44.1, 50.1) during the second year after vaccination, and then waned more gradually through year 8, when VE was 31.8% (95% CI: 15.1, 45.2). Unexpectedly, VE in persons vaccinated when they were aged 80 years or older was similar to VE in younger vaccinees, and VE in persons vaccinated when immune compromised was similar to VE in persons vaccinated when immune competent.

Waning protection following 5 doses of a 3-component diphtheria, tetanus, and acellular pertussis vaccine

BACKGROUND The effectiveness of diphtheria, tetanus, and acellular pertussis (DTaP) vaccines wanes substantially after the 5th dose given at ages 4-6years, but has not been described following 5 doses of the same type of DTaP vaccine. We investigated waning effectiveness against pertussis in California over nearly 10years, which included large pertussis outbreaks, following 5 doses of GSK DTaP vaccines (DTaP3). METHODS We conducted a case-control study (NCT02447978) of children who received 5 doses of DTaP at Kaiser Permanente Northern California from 01/2006 through 03/2015. We compared time since the 5th dose in confirmed pertussis polymerase chain reaction (PCR)-positive cases with pertussis PCR-negative controls. We used logistic regression adjusted for calendar time, age, sex, race, and service area to estimate the effect of time since the 5th DTaP dose on the odds of pertussis. Our primary analysis evaluated waning after 5 doses of DTaP3. We also examined waning after 5 doses of any type of DTaP vaccines. RESULTS Our primary analysis compared 340 pertussis cases diagnosed at ages 4-12years with 3841 controls. The any DTaP analysis compared 462 pertussis cases with 5649 controls. The majority of all DTaP doses in the study population were DTaP3 (86.8%). Children who were more remote from their 5th dose were less protected than were children whose 5th dose was more recent; the adjusted odds of pertussis increased by 1.27 per year (95% CI 1.10, 1.46) after 5 doses of DTaP3 and by 1.30 per year (95% CI 1.15, 1.46) after any 5 DTaP vaccines doses. CONCLUSIONS Waning protection after DTaP3 was similar to that following 5 doses of any type of DTaP vaccines. This finding is not unexpected as most of the DTaP vaccines administered were DTaP3. Following 5 doses of DTaP3 vaccines, protection from pertussis waned 27% per year on average. NCT number: NCT02447978.

Effectiveness of Live Zoster Vaccine in Preventing Herpes Zoster Ophthalmicus (HZO)

Abstract Background Herpes zoster ophthalmicus (HZO), caused by reactivation of varicella-zoster virus in or around the eye, can be severe and often results in care-seeking that may be less discretionary than for uncomplicated herpes zoster (HZ). We compared the vaccine effectiveness (VE) of live zoster vaccine against HZO with the VE against HZ overall. Methods Kaiser Permanente Northern California (KPNC) members enter the ongoing cohort study when age-eligible for zoster vaccine starting in 2007. Incident HZ was defined as a new diagnosis of HZ with an antiviral prescription or a positive varicella viral test. Among those, an HZO case was defined as having an HZO diagnosis during an ophthalmology visit within 30 days of the initial HZ diagnosis. VE by age at vaccination and time since vaccination was estimated using Cox regression adjusted for age, race, sex and time-varying measures of healthcare use, comorbidities and immunocompromise status. Average VE over the first 5 years following vaccination was calculated as a weighted average of annual VE estimates. Results During 2007–2014, ~1.3 million individuals ≥50 years of age entered the study population and 29% were vaccinated. Among 48,889 incident HZ cases, 2,858 (6%) had HZO, 87% of whom were unvaccinated. For all ages combined, VE against HZO was 72% (95% CI, 64%-79%) in year 1, similar to 68% (95% CI, 65%-70%) against HZ. VE fell in years 2, 3, 4, and 5 to 47%, 45%, 42% and 27% for HZO and to 47%, 39%, 41% and 37% for HZ. For age groups 60 – 69 and 70 – 79, where we have the most data, initial VE and waning were similar for HZO and HZ. Numbers of HZO cases for 50–59 year olds were too small to evaluate at this time. Average VE against HZO over the first 5 years following vaccination was 52% (95% CI, 42%–60%) for ages 60–69, 51% (95% CI, 39%–61%) for ages 70-79, and 39% (95% CI, 14%-57%) for ages 80+; similarly, 5-year average VE against HZ was 49%, 46%, and 44% for these 3 age groups. Conclusion VE against HZO was similar to VE against HZ regardless of age at vaccination or time since vaccination. Effectiveness of live zoster vaccine in preventing HZO was highest in year one with subsequent waning. Disclosures E. Earley, Merck & Co.: Research Contractor, Salary; M. Marks, Merck and Co. Inc.: Employee, Restricted Stock and Salary; P. Saddier, Merck & Co., Inc.: Employee, Salary; N. P. Klein, GSK: Investigator, Grant recipient; sanofi pasteur: Investigator, Grant recipient; Merck & Co.: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Science: Investigator, Grant recipient Pfizer: Investigator, Grant recipient