Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members.

OBJECTIVES: To evaluate the rates of myopericarditis (primary objective) and rates of cardiovascular and neurological adverse events (secondary objectives) in temporal association with ACAM2000® smallpox vaccine. METHODS: Observational cohort study conducted through monthly surveillance from 2009 to 2017 of electronic medical records of military service members (SM) for pre-specified cardiac and neurological International Classification of Diseases (ICD) codes reported in the 30 days following smallpox vaccination. ICD codes potentially predictive of myopericarditis and codes for encephalitis, Guillain-Barré syndrome, and sudden death were classified into Group 1. All other cardiovascular and neurological ICD codes were classified into Group 2. Medical records containing Group 1 codes were individually reviewed to confirm coding accuracy and to seek additional data in support of myopericarditis adjudication, which was performed by an independent clinical panel. Chart reviews were not performed for Group 2 codes, which were reported in aggregate only. RESULTS: 897,227 SM who received ACAM2000 smallpox vaccine and 450,000 SM who received Dryvax smallpox vaccine were included in the surveillance population. The rate of adjudicated myopericarditis among ACAM2000 smallpox vaccine recipients was 20.06/100,000 and was significantly higher for males (21.8/100,000) than females (8.5/100,000) and for those < 40 years of age (21.1/100,000) than for those 40 years or older (6.3/100,000). Overall rates for any cardiovascular event (Group 1 plus Group 2) were 113.5/100,000 for ACAM2000 vaccine and 439.3/100,000 for Dryvax vaccine; rate ratio, 0.26 (95% CI, 0.24-0.28). The rates of subjects with one or more defined neurological events were 2.12/100,000 and 1.11/100,000 for ACAM2000 and Dryvax vaccines respectively; rate ratio, 1.91 (95% CI, 0.71-5.10). CONCLUSIONS: Electronic records surveillance of the entire vaccinated SM population over a ten-year period found rates of myopericarditis, of defined neurological events, and of overall cardiac events that were consistent with those of prior passive surveillance studies involving Dryvax or ACAM2000 smallpox vaccines. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00927719.

Prospective safety surveillance study of ACAM2000 smallpox vaccine in deploying military personnel.

OBJECTIVES: To compare rates of myopericarditis, severe and serious dermatological or neurological events, and other adverse events in deploying US military personnel who received or did not receive ACAM2000® (Smallpox [Vaccinia] Vaccine, Live) vaccine and to evaluate potential risk factors for development of myopericarditis. METHODS: Prospective observational cohort study enrolling up to 15,000 ACAM2000 recipients (Cohort 1) and up to 5000 persons otherwise eligible for ACAM2000 vaccination but not vaccinated due to recency of vaccination or characteristics of their contacts (Cohort 2). Data and specimens were collected initially and 10 (6-17) days later. Those with clinical or laboratory evidence of possible myopericarditis were referred for further evaluation and adjudication by a blinded independent review committee. The adjusted odds ratio for myopericarditis was determined by a logistic regression model controlling for age, race, gender, and exercise regimen. RESULTS: 14,667 subjects provided initial data and specimens (Cohort 1, 10,825; Cohort 2, 3842); 12,110 (Cohort 1, 8945; Cohort 2, 3165) completed Visit 2 per-protocol. A total of 125 (Cohort 1, 111; Cohort 2, 14) were referred for myopericarditis adjudication, yielding 54 (Cohort 1, 44, Cohort 2, 10) subclinical myopericarditis, 5 suspected myocarditis, 1 confirmed myocarditis, and 1 suspected pericarditis. Unadjusted myopericarditis rates were: Cohort 1, 5.7/1000 (95% CI, 4.3-7.5); Cohort 2, 3.2/1000 (95% CI, 1.7-5.8). Unadjusted and adjusted odds ratios for myopericarditis were 1.8 (95% CI: 0.9-3.6) and 1.3 (95% CI: 0.6-2.6), respectively. One hundred seventeen subjects (1.1%) in Cohort 1 and 13 (0.3%) in Cohort 2 experienced at least 1 serious adverse event. No instances of serious and severe neurological or dermatological adverse events were reported. CONCLUSIONS: In this carefully screened, generally young and healthy service-member population, ACAM2000 vaccination was associated with modest non-significant increases in the risk of myopericarditis (adjusted OR, 1.3; unadjusted OR, 1.8); all but seven cases were subclinical. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00928577.

Prevention and control of influenza and dengue through vaccine development.

Influenza and dengue are viral illnesses of global public health importance, especially among children. Accordingly, these diseases have been the focus of efforts to improve their prevention and control. Influenza vaccination offers the best protection against clinical disease caused by strains contained within the specific year's formulation. It is not uncommon for there to be a mismatch between vaccine strains and circulating strains, particularly with regards to the B lineages. For more than a decade, two distinct lineages of influenza B (Yamagata and Victoria) have co-circulated in the US with varying frequencies, but trivalent influenza vaccines contain only one B-lineage strain and do not offer adequate protection against the alternate B-lineage. Quadrivalent influenza vaccines (QIVs), containing two A strains (H1N1 and H3N2) and two B strains (one from each lineage) have been developed to help protect against the four strains predicted to be the most likely to be circulating. The QIV section of this article discusses epidemiology of pediatric influenza, importance of influenza B in children, potential benefits of QIV, and new quadrivalent vaccines. In contrast to influenza, a vaccine against dengue is not yet available in spite of many decades of research and development. A global increase in reports of dengue fever (DF) and its more severe presentations, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), suggest that US physicians will increasingly encounter patients with this disease. Similarities of the early signs and symptoms of influenza and dengue and the differences in disease management necessitates a better understanding of the epidemiology, clinical presentation, management, and prevention of DF by US physicians, including pediatricians. The article also provides a brief overview of dengue and discusses dengue vaccine development.

Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research.

BACKGROUND: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule against falciparum malaria would be compatible with the Expanded Programme on Immunization, or in combination with other prevention measures, interrupt epidemic malaria or protect individuals upon sudden travel to an endemic area. METHODS: We conducted an open label, Phase 2a trial of two different full dose schedules of RTS,S/AS02 in 40 healthy malaria-naïve adults. Cohort 1 (n=20) was immunized on a 0, 1, and 3 month schedule and Cohort 2 (n=20) on a 0, 7, and 28 day schedule. Three weeks later, 38 vaccinees and 12 unimmunized infectivity controls underwent malaria challenge. RESULTS: Both regimens had a good safety and tolerability profile. Peak GMCs of antibody to the circumsporozoite protein (CSP) were similar in Cohort 1 (78 microg/mL; 95% CI: 45-134) and Cohort 2 (65 microg/mL; 95% CI: 40-104). Vaccine efficacy for Cohort 1 was 45% (95% CI: 18-62%) and for Cohort 2, 39% (95% CI: 11-56%). Protected volunteers had a higher GMC of anti-CSP antibody (114 microg/mL) than did volunteers with a 2-day delay (70 microg/mL) or no delay (30 microg/mL) in the time to onset of parasitemia (Kruskal-Wallis, p=0.019). A trend was seen for higher CSP-specific IFN-gamma responses in PBMC from protected volunteers only in Cohort 1, but not in Cohort 2, for ex vivo and for cultured ELISPOT assays. CONCLUSION: In malaria-naïve adults, the efficacy of three-dose RTS,S/AS02 regimens on either a 0, 1, and 3 month schedule or an abbreviated 0, 7, and 28 day schedule was not discernibly different from two previously reported trials of two-dose regimens given at 0, 1 month that conferred 47% (95% CI: -19 to 76%) protection and in another trial 42% (95% CI: 5-63%). A strong association of CSP-specific antibody with protection against malaria challenge is observed and confirms similar observations made in other studies. Subsequent trials of adjuvanted RTS,S in African children and infants on a 0, 1, and 2 month schedule have demonstrated a favorable safety and efficacy profile.

Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites.

During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.