Hung Fu Tseng

Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011.

In fall 2010 in the southern hemisphere, an increased risk of febrile seizures was noted in young children in Australia in the 24 h after receipt of trivalent inactivated influenza vaccine (TIV) manufactured by CSL Biotherapies. Although the CSL TIV vaccine was not recommended for use in young children in the US, during the 2010-2011 influenza season near real-time surveillance was conducted for febrile seizures in the 0-1 days following first dose TIV in a cohort of 206,174 vaccinated children ages 6 through 59 months in the Vaccine Safety Datalink Project. On a weekly basis, surveillance was conducted with the primary approach of a self-controlled risk interval design and the secondary approach of a current vs. historical vaccinee design. Sequential statistical methods were employed to account for repeated analyses of accumulating data. Signals for seizures based on computerized data were identified in mid November 2010 using a current vs. historical design and in late December 2010 using a self-controlled risk interval design. Further signal evaluation was conducted with chart-confirmed febrile seizure cases using only data from the primary approach (i.e. self-controlled risk interval design). The magnitude of the incidence rate ratio and risk difference comparing risk of seizures in the 0-1 days vs. 14-20 days following TIV differed by receipt of concomitant 13-valent pneumococcal conjugate vaccine (PCV13). Among children 6-59 months of age, the incidence rate ratio (IRR) for TIV adjusted for concomitant PCV13 was 2.4 (95% CI 1.2, 4.7) while the IRR for PCV13 adjusted for concomitant TIV was 2.5 (95% CI 1.3, 4.7). The IRR for concomitant TIV and PCV13 was 5.9 (95% CI 3.1, 11.3). Risk difference estimates varied by age due to the varying baseline risk for seizures in young children, with the highest estimates occurring at 16 months (12.5 per 100,000 doses for TIV without concomitant PCV13, 13.7 per 100,000 doses for PCV13 without concomitant TIV, and 44.9 per 100,000 doses for concomitant TIV and PCV13) and the lowest estimates occurring at 59 months (1.1 per 100,000 doses for TIV without concomitant PCV13, 1.2 per 100,000 doses for PCV13 without concomitant TIV, and 4.0 per 100,000 doses for concomitant TIV and PCV13). Incidence rate ratio and risk difference estimates were lower for children receiving TIV without concomitant PCV13 or PCV13 without concomitant TIV. Because of the importance of preventing influenza and pneumococcal infections and associated complications, our findings should be placed in a benefit-risk framework to ensure that population health benefits are maximized.

Vaccines and the Risk of Multiple Sclerosis and Other Central Nervous System Demyelinating Diseases

IMPORTANCE Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health. OBJECTIVE To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS. DESIGN, SETTING, AND PARTICIPANTS A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code. EXPOSURES Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system. MAIN OUTCOMES AND MEASURES All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset. RESULTS We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57). CONCLUSIONS AND RELEVANCE We found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy.

Declining Effectiveness of Herpes Zoster Vaccine in Adults Aged ≥60 Years

Understanding long-term effectiveness of herpes zoster (HZ) vaccine is critical for determining vaccine policy. 176 078 members of Kaiser Permanente ≥60 years vaccinated with HZ vaccine and three matched unvaccinated members were included. Hazard ratios and 95% confidence intervals (CIs) associated with vaccination at each year following vaccination were estimated by Cox regression model. The effectiveness of HZ vaccine decreased from 68.7% (95% CI, 66.3%-70.9%) in the first year to 4.2% (95% CI, -24.0% to 25.9%) in the eighth year. This rapid decline in effectiveness of HZ vaccine suggests that a revaccination strategy may be needed, if feasible.

Incidence of herpes zoster among children vaccinated with varicella vaccine in a prepaid health care plan in the United States, 2002-2008.

Background: Herpes zoster (HZ), or shingles, is caused by reactivation of latent varicella-zoster virus after a primary infection with either wild-type or vaccine-type varicella-zoster virus, the latter having been introduced in 1995 for children. Since then, few population-based data about the incidence of childhood HZ are available. Methods: We identified children aged ≤12 years who were vaccinated with 1 dose of varicella vaccine between 2002 and 2008 in a prepaid health plan and followed them through their electronic health records for a diagnosis of HZ. The medical records of these children were reviewed. Persistent and chronic conditions for these children before HZ were identified. Results: There were 172,163 children vaccinated, with overall follow-up of 446,027 person-years (Incidence rate = 27.4 per 100,000 person-years, 95% confidence interval: 22.7–32.7). Children vaccinated after age 5 years had a higher but not statistically significant different rate than children vaccinated between 12 and 18 months (34.3 vs. 28.5 per 100,000 person-years). Among children vaccinated between 12 and 18 months, incidence rates gradually increased each year in the first 4 years after vaccination (P < 0.001). Among the HZ cases, there were 1 (0.7%) case of lymphoid leukemia, 1 (0.7%) case of drug abuse, 16 (11.1%) cases of asthma with 3 or more acute exacerbations, 12 (8.3%) cases of developmental disorders, and 3 (2.1%) cases of psychological or mental disorders. Conclusions: These data demonstrate that diagnosed HZ is rare among children following varicella vaccine. Despite the small numbers, the roles of delayed vaccination, severe asthma, and development disorders warrant further investigation. In the future, analyses of HZ isolates will be needed to identify the virus strains causing reactivation.

Herpes Zoster Vaccine and the Incidence of Recurrent Herpes Zoster in an Immunocompetent Elderly Population

BACKGROUND The benefit of vaccinating immunocompetent patients who have had shingles has not been examined. The study assessed the association between vaccination and the incidence of herpes zoster recurrence among persons with a recent episode of clinically diagnosed herpes zoster. METHODS This is a matched cohort study in Kaiser Permanente Southern California. Study populations were immunocompetent elderly individuals ≥ 60 years old with a recent episode of herpes zoster. Incidence of recurrent herpes zoster was compared between the vaccinated and the unvaccinated matched cohorts. RESULTS A total of 1036 vaccinated and 5180 unvaccinated members were included. On the basis of clinically confirmed cases, the incidence of recurrent herpes zoster among persons aged <70 years was 0.99 (95% confidence interval [CI], .02-5.54) and 2.20 (95% CI, 1.10-3.93) cases per 1000 person-years in the vaccinated and unvaccinated cohorts, respectively. The adjusted hazard ratio was 0.39 (95% CI, .05-4.45) among persons aged <70 years and 1.05 (95% CI, .30-3.69) among persons aged ≥ 70 years. CONCLUSIONS The risk of herpes zoster recurrence following a recent initial episode is fairly low among immunocompetent adults, regardless of vaccination status. Such a low risk suggests that one should evaluate the necessity of immediately vaccinating immunocompetent patients who had a recent herpes zoster episode.

Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study

Abstract.  Tseng HF, Liu A, Sy L, Marcy SM, Fireman B, Weintraub E, Baggs J, Weinmann S, Baxter R, Nordin J, Daley MF, Jackson L, Jacobsen SJ, for the Vaccine Safety Datalink (VSD) Team (Kaiser Permanente, Pasadena, CA; Kaiser Permanente, Oakland, CA; Centers for Disease Control and Prevention, Atlanta, GA; Kaiser Permanente, Portland, OR; HealthPartners Research Foundation, Minneapolis, MN; Kaiser Permanente, Denver, CO; and Group Health Cooperative of Puget Sound, Seattle, WA; USA). Safety of zoster vaccine in adults from a large managed‐care cohort: a Vaccine Safety Datalink study. J Intern Med 2012; 271: 510–520.

Evaluation of the incidence of herpes zoster after concomitant administration of zoster vaccine and polysaccharide pneumococcal vaccine.

In 2009, a revision to the zoster vaccine package insert was approved stating that the zoster vaccine and the pneumococcal vaccine should not be given concurrently because concomitant use resulted in reduced immunogenicity of the zoster vaccine. We conducted an observational study to evaluate if concomitant vaccination reduces the protective effect of the zoster vaccine. The study was conducted in Kaiser Permanente Southern California. Incidence of herpes zoster (HZ) after vaccination with a zoster vaccine in the population receiving both vaccines on the same day was compared to that in the population receiving a pneumococcal vaccine within one year to 30 days prior to zoster vaccine. Vaccinations and incident HZ cases were identified by electronic health records. The hazard ratio for incident HZ associated with concomitant vs. nonconcomitant vaccination was estimated using the Cox proportional hazard model. There were 56 incident HZ cases in the concomitant vaccination cohort and 58 in the nonconcomitant vaccination cohort, yielding a HZ incidence of 4.54 (95% confidence interval [CI], 3.43-5.89) and 4.51 (95% CI, 3.42-5.83) per 1000 person-years, respectively. The hazard ratio comparing the incidence rate of HZ in the two cohorts was 1.19 (95% CI, 0.81-1.74) in the adjusted analysis. In this study, we found no evidence of an increased risk of HZ in the population receiving zoster vaccine and pneumococcal vaccine concomitantly. The revision of the product information needs to be carefully assessed to avoid introducing barriers to patients and providers who are interested in these two important vaccines.

Vaccination Against Zoster Remains Effective in Older Adults Who Later Undergo Chemotherapy

BACKGROUND Approximately 40% of adults develop invasive cancer during their lifetimes, many of whom require chemotherapy. Herpes zoster (HZ) is common and often severe in patients undergoing chemotherapy, yet there are no data regarding whether these patients retain specific protection against HZ if they had previously received zoster vaccine. We conducted a study to determine whether zoster vaccine was effective in patients who subsequently underwent chemotherapy. METHODS The cohort study consisted of Kaiser Permanente Southern California members aged ≥60 years treated with chemotherapy. The exposure variable was receipt of zoster vaccine prior to initiation of chemotherapy. Incident HZ cases were identified using International Classification of Diseases, Ninth Revision diagnostic codes. HZ incidence rates were calculated; hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. RESULTS There were 91 and 583 HZ cases in the vaccinated and unvaccinated cohorts, respectively, yielding an incidence rate of 12.87 (95% CI, 10.48-15.80) vs 22.05 (95% CI, 20.33-23.92) per 1000 person-years. Thirty-month cumulative incidence was 3.28% in the vaccinated group and 5.34% in the unvaccinated group (P < .05). The adjusted HR for HZ was 0.58 (95% CI, .46-.73) and showed no significant variation by age, sex, or race. HZ incidence rates remained increased in the small subgroup of persons receiving zoster vaccine within 60 days before chemotherapy, but this was the only group affected by indication bias. No vaccinated patients underwent hospitalization for HZ, compared with 6 unvaccinated patients. CONCLUSIONS Zoster vaccine continues to protect against HZ if recipients later undergo chemotherapy. Our findings provide an additional rationale for offering zoster vaccine to indicated adults while they are immunocompetent.

Postlicensure surveillance for pre-specified adverse events following the 13-valent pneumococcal conjugate vaccine in children

Although no increased risk was detected for serious adverse events in the prelicensure trials for the 13-valent pneumococcal vaccine, Prevnar 13(®) (PCV13), continued monitoring of rare but serious adverse events is necessary. A surveillance system using cohort study design was set up to monitor safety of PCV13 immediately after it was included in the childhood immunization program in the United States. The exposed population included children of 1 month to 2 years old who received PCV13 from April, 2010 to January, 2012 from the eight managed care organizations participating in the Vaccine Safety Datalink Project in the United States. The historical unexposed population was children of the same age who received the 7-valent pneumococcal conjugate vaccine Prevnar 7(®) (PCV7) in 2007 (or 2005 depending on the outcome of interest) to 2009. The risk of pre-specified adverse events in the risk window following PCV13 was repeatedly compared to that in the historical comparison group. The number of doses included in the study was 599,229. No increased risk was found for febrile seizures, urticaria or angioneurotic edema, asthma, thrombocytopenia, or anaphylaxis. An increased risk for encephalopathy was not confirmed following the medical record review. The relative risk for Kawasaki disease in 0-28 days following vaccination was 1.94 (95% confidence interval: 0.79-4.86), comparing PCV13 to PCV7. Comparing to PCV7 vaccine, we identified no significant increased risk of pre-specified adverse events in the Vaccine Safety Datalink study cohort. The possible association between PCV13 and Kawasaki disease may deserve further investigation.

Herpes Zoster Caused by Vaccine-Strain Varicella Zoster Virus in an Immunocompetent Recipient of Zoster Vaccine

We report the first laboratory-documented case of herpes zoster caused by the attenuated varicella zoster virus (VZV) contained in Zostavax in a 68-year-old immunocompetent adult with strong evidence of prior wild-type VZV infection. The complete genome sequence of the isolate revealed that the strain carried 15 of 42 (36%) recognized varicella vaccine-associated single-nucleotide polymorphisms, including all 5 of the fixed vaccine markers present in nearly all of the strains in the vaccine. The case of herpes zoster was relatively mild and resolved without complications.