Safety and immunogenicity of an inactivated eastern equine encephalitis virus vaccine.

BACKGROUND: Eastern equine encephalitis virus (EEEV) is a mosquito borne alphavirus spread primarily in Atlantic and Gulf Coast regions of the United States. EEEV is the causative agent of a devastating meningoencephalitis syndrome, with approximately 30% mortality and significant morbidity. There is no licensed human vaccine against EEEV. An inactivated EEEV vaccine has been offered under investigational new drug (IND) protocols at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. METHODS: Healthy at-risk laboratory personnel received inactivated PE-6 strain EEEV (TSI-GSD 104) vaccine under two separate IND protocols. Protocol FY 99-11 (2002-2008) had a primary series consisting of doses on day 0, 7, and 28. Protocol FY 06-31 (2008-2016) utilized a primary series with doses on day 0 and 28, and month 6. Participants with an inadequate immune response, plaque reduction neutralization test with 80% cut-off (PRNT80) titer < 40, received booster vaccination. Volunteers with prior EEEV vaccination were eligible to enroll for booster doses based on annual titer evaluation. RESULTS: The FY06-31 dosing schema resulted in significantly greater post-primary series immune response (PRNT80 ≥ 40) rates (84% vs 54%) and geometric mean titers (184.1 vs 39.4). The FY 06-31 dosing schema also resulted in significantly greater cumulative annual immune response rates from 1 to up to 7 years post vaccination (75% vs 59%) and geometric mean of titers (60.1 vs 43.0). The majority of probably or definitely related adverse events were mild and local; there were no probably or definitely related serious adverse events. CONCLUSIONS: Inactivated PE-6 EEEV vaccine is safe and immunogenic in at-risk laboratory personnel. A prolonged primary series, with month 6 dose, significantly improved vaccine immunogenicity both post-primary series and longitudinally on annual titers. Despite decades of safe use under IND, full licensure is not planned due to manufacturing constraints, and ongoing development of alternatives.

Immune interference in the setting of same-day administration of two similar inactivated alphavirus vaccines: eastern equine and western equine encephalitis.

We compared the effect on primary vaccination plaque-reduction neutralization 80% titers (PRNT80) responses of same-day administration (at different injection sites) of two similar investigational inactivated alphavirus vaccines, eastern equine encephalitis (EEE) vaccine (TSI-GSD 104) and western equine encephalitis (WEE) vaccine (TSI-GSD 210) to separate administration. Overall, primary response rate for EEE vaccine was 524/796 (66%) and overall primary response rate for WEE vaccine was 291/695 (42%). EEE vaccine same-day administration yielded a 59% response rate and a responder geometric mean titer (GMT)=89 while separate administration yielded a response rate of 69% and a responder GMT=119. WEE vaccine same-day administration yielded a 30% response rate and a responder GMT=53 while separate administration yielded a response rate of 54% and a responder GMT=79. EEE response rates for same-day administration (group A) vs. non-same-day administration (group B) were significantly affected by gender. A logistic regression model predicting response to EEE comparing group B to group A for females yielded an OR=4.10 (95% CL 1.97-8.55; p=.0002) and for males yielded an OR=1.25 (95% CL 0.76-2.07; p=.3768). WEE response rates for same-day administration vs. non-same-day administration were independent of gender. A logistic regression model predicting response to WEE comparing group B to group A yielded an OR=2.14 (95% CL 1.22-3.73; p=.0077). We report immune interference occurring with same-day administration of two completely separate formalin inactivated viral vaccines in humans. These findings combined with the findings of others regarding immune interference would argue for a renewed emphasis on studying the immunological mechanisms of induction of inactivated viral vaccine protection.

A Phase 1 clinical trial of Hantaan virus and Puumala virus M-segment DNA vaccines for hemorrhagic fever with renal syndrome.

Candidate DNA vaccines for hemorrhagic fever with renal syndrome expressing the envelope glycoprotein genes of Hantaan (HTNV) or Puumala (PUUV) viruses were evaluated in an open-label, single-center Phase 1 study consisting of three vaccination groups of nine volunteers. The volunteers were vaccinated by particle-mediated epidermal delivery (PMED) three times at four-week intervals with the HTNV DNA vaccine, the PUUV DNA vaccine or both vaccines. At each dosing, the volunteers received 8 µg DNA/4 mg gold. There were no study-related serious adverse events, and all injection site pain was graded as mild. The most commonly reported systemic adverse events were fatigue, headache, malaise, myalgia, and lymphadenopathy. Blood samples were collected on days 0, 28, 56, 84, 140, and 180, and assayed for the presence of neutralizing antibodies. In the single vaccine groups, neutralizing antibodies to HTNV or PUUV were detected in 30% or 44% of individuals, respectively. In the combined vaccine group, 56% of the volunteers developed neutralizing antibodies to one or both viruses. These results demonstrate that the HTNV and PUUV DNA vaccines are safe and can be immunogenic in humans when delivered by PMED.

Immunogenicity and safety of an inactivated Rift Valley fever vaccine in a 19-year study.

An investigational, formalin-inactivated Rift Valley fever (RVF) vaccine, known as The Salk Institute-Government Services Division (TSI-GSD) 200 vaccine, was administered to 1860 at-risk subjects (5954 doses) between 1986 and 2004 as a three-dose primary series (days 0, 7, and 28) followed by booster doses as needed for declining titers. An initial positive serological response (PRNT(80)≥1:40) to the primary series was observed in 90% of subjects. Estimate of the PRNT(80) response half-life in initial responders to the primary series by Kaplan-Meier plot was 315 days after the primary series dose 3. Differences in a serological response were observed at 2 weeks after dose 3 of the primary series between vaccine lots and for gender (women>men); a trend was observed for age (<40 years). When response to the primary series was measured by PRNT(50) titer ≥1:40, nearly all subjects (99.1%) responded. In individuals not initially responding to the primary series (PRNT(80)<1:40), a response was observed in most subjects after receiving only one booster dose. Immune response (all subjects) to subsequent booster doses for a declining titer (PRNT(80)<1:40) was 98.4%. The vaccine was well-tolerated; vaccine-related adverse reactions were generally mild and self-limited. Differences in adverse events were observed with vaccine lot and sex. The data support the safety and immunogenicity of the inactivated RVF vaccine, and may serve as a standard of comparison for immunogenicity and safety for future RVF vaccines.

Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea.

Results of a clinical study using intravenous (IV) ribavirin for treating Department of Defense personnel with hemorrhagic fever with renal syndrome (HFRS) acquired in Korea from 1987 to 2005 were reviewed to determine the clinical course of HFRS treated with IV ribavirin. A total of 38 individuals enrolled in the study had subsequent serological confirmation of HFRS. Four of the 38 individuals received three or fewer doses of ribavirin and were excluded from treatment analysis. Of the remaining 34 individuals, oliguria was present in one individual at treatment initiation; none of the remaining 33 subjects developed oliguria or required dialysis. The mean peak serum creatinine was 3.46 mg/dl and occurred on day 2 of ribavirin therapy. Both the peak serum creatinine and the onset of polyuria occurred on mean day 6.8 of illness. Reversible hemolytic anemia was the main adverse event of ribavirin, with a >or=25% decrease in hematocrit observed in 26/34 (76.5%) individuals. While inability to adjust for all baseline variables prevents comparison to historical cohorts in Korea where oliguria has been reported in 39-69% cases and dialysis required in approximately 40% HFRS cases caused by Hantaan virus, the occurrence of 3% oliguria and 0% dialysis requirement in the treatment cohort is supportive of a previous placebo-controlled HFRS trial in China where IV ribavirin given early resulted in decreased occurrence of oliguria and decreased severity of renal insufficiency.

Laboratory exposures to staphylococcal enterotoxin B.

Staphylococcal enterotoxins are 23- to 29-kDa polypeptides in the bacterial superantigen protein family. Clinical symptoms from intoxication with staphylococcal enterotoxins vary by exposure route. Ingestion results in gastrointestinal symptoms, and inhalation results in fever as well as pulmonary and gastrointestinal symptoms. Review of occupational exposures at the U.S. Army Medical Research Institute of Infectious Diseases from 1989 to 2002 showed that three laboratory workers had symptoms after ocular exposure to staphylococcal enterotoxin B (SEB). Conjunctivitis with localized cutaneous swelling occurred in three persons within 1 to 6 hours after exposure to SEB; two of these persons also had gastrointestinal symptoms, which suggests that such symptoms occurred as a result of exposure by an indirect cutaneous or ocular route. Ocular exposures from SEB resulting in conjunctivitis and localized swelling have not previously been reported. Symptoms from these patients and review of clinical symptoms of 16 laboratory-acquired inhalational SEB intoxications may help healthcare workers evaluate and identify SEB exposures in laboratory personnel at risk.

Management guidelines for laboratory exposures to agents of bioterrorism.

Over the past several years, funding for biodefense research has increased dramatically, leading to the possibility of increased laboratory-acquired infections with potential bioterrorism agents. The Special Immunizations Program at United States Army Medical Research Institute of Infectious Diseases reviewed its policy and management of potential occupational exposures (1989-2002) to assess guidelines for determining the risk of exposure and disease and to determine criteria for initiating postexposure prophylaxis (PEP). Initiating antibiotic PEP was based primarily on exposure risk but was also influenced by vaccination status and agent virulence. PEP was given to nearly all moderate- and high-risk bacterial exposures, regardless of vaccination status, to most unvaccinated and subsets of vaccinated minimal-risk exposures, but generally not to negligible-risk exposures. Algorithms for evaluating and managing potential exposures are presented to provide guidance to other agencies as they begin to work with these agents.

Experience in the medical management of potential laboratory exposures to agents of bioterrorism on the basis of risk assessment at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID).

Experience in managing laboratory exposures to potential agents of bioterrorism is limited. The United States Army Medical Research Institute of Infectious Diseases reviewed laboratory exposures involving these agents (1989 to 2002) to assess the effectiveness of medical management. The evaluation of 234 persons (78% vaccinated) for exposure to 289 infectious agents revealed 5 confirmed infections (glanders, Q fever, vaccinia, chikungunya, and Venezuelan equine encephalitis). Postexposure antibiotic prophylaxis was given for most moderate- or high-risk bacterial exposures (41/46; 89%); most unvaccinated minimal-risk (7/10; 70%), and subsets of vaccinated minimal-risk exposures (18/53; 34%) but generally not negligible-risk exposures (6/38; 16%). Vaccine "breakthroughs" were not unexpected (enzootic Venezuelan equine encephalitis, localized vaccinia) or presented with mild symptoms (Q fever). A multifaceted policy of personal protective measures, vaccination, early assessment, and postexposure antibiotic prophylaxis was effective in minimizing morbidity and mortality in at-risk laboratory workers.

Risk of occupationally acquired illnesses from biological threat agents in unvaccinated laboratory workers.

Many vaccines for bioterrorism agents are investigational and therefore not available (outside of research protocol use) to all at-risk laboratory workers who have begun working with these agents as a result of increased interest in biodefense research. Illness surveillance data archived from the U.S. offensive biological warfare program (from 1943 to 1969) were reviewed to assess the impact of safety measures on disease prevention (including biosafety cabinets [BSCs]) before and after vaccine availability. Most laboratory-acquired infections from agents with higher infective doses (e.g., anthrax, glanders, and plague) were prevented with personal protective measures and safety training alone. Safety measures (including BSCs) without vaccination failed to sufficiently prevent illness from agents with lower infective doses in this high-risk research setting. Infections continued with tularemia (average 15/year), Venezuelan equine encephalitis (1.9/year), and Q fever (3.4/year) but decreased dramatically once vaccinations became available (average of 1, 0.6, and 0 infections per year, respectively). While laboratory-acquired infections are not expected to occur frequently in the current lower-risk biodefense research setting because of further improvements in biosafety equipment and changes in biosafety policies, the data help to define the inherent risks of working with the specific agents of bioterrorism. The data support the idea that research with these agents should be restricted to laboratories with experience in handling highly hazardous agents and where appropriate safety training and precautions can be implemented.