Phillip R. Pittman

Long-term duration of detectable neutralizing antibodies after administration of live-attenuated VEE vaccine and following booster vaccination with inactivated VEE vaccine

The US Army successfully developed a live-attenuated Venezuelan Equine Encephalitis (VEE) vaccine, TC-83, in 1961, and subsequently developed a formalin-inactivated vaccine, C-84, in 1974. Initial evaluation of both vaccines was promising, but no long-term safety and immunogenicity data have been reported. This study is the first analysis of the long-term safety and immunogenicity of TC-83 and C-84. From January 1976 to December 1990, 821 laboratory workers at the USAMRIID were vaccinated with a single 0.5 ml subcutaneous (s.c.) dose of TC-83; 128 were boosted with a single 0.5 ml s.c. dose of C-84. Eighty-two per cent of vaccinees responded to TC-83 with an 80% plaque reduction neutralization titer (PRNT80) of > or = 1:20. Minor side-effects were noted in 23% of vaccinees. No long-term sequelae were recorded. Kaplan-Meier analysis showed a 60% probability of vaccinees maintaining a PRNT80 of > or = 1:20 for 5.5-8 years. C-84 was given to two groups: 76 initial nonresponders to TC-83, Group A, and 52 initial responders to TC-83 whose PRNT80 became < 1:20 over time, Group B. C-84 successfully boosted 76% of Group A and 100% of Group B to a PRNT80 > or = 1:20 Kaplan-Meier analysis showed 100% probability of Group B members maintaining a titer of > or = 1:20 for the duration of follow-up, which, in some cases, exceeded 10 years; while Group A had only a 60% probability of maintaining a titer for 1-2 years. Only minor local reactions to C-84 were noted in 6.3% of vaccinees. We conclude that, although TC-83 is reactogenic, when administered as the primary vaccine and C-84 is administered as a boost, these vaccines provide good long-term immunity and are safe in humans. However, a single dose vaccine that is more immunogenic and less reactogenic is needed.

Anthrax vaccine: immunogenicity and safety of a dose-reduction, route-change comparison study in humans.

Anthrax vaccine adsorbed (AVA), an effective countermeasure against anthrax, is administered as six subcutaneous (SQ) doses over 18 months. To optimize the vaccination schedule and route of administration, we performed a prospective pilot study comparing the use of fewer AVA doses administered intramuscularly (IM) or SQ with the current schedule and route. We enrolled 173 volunteers, randomized to seven groups, who were given AVA once IM or SQ; two doses, 2 or 4 weeks apart, IM or SQ; or six doses at 0, 2, 4 weeks and 6, 12, and 18 months (control group, licensed schedule and route). IM administration of AVA was associated with fewer injection site reactions than SQ administration. Following the first SQ dose of AVA, compared to males, females had a significantly higher rate of injection site reactions such as erythema, induration and subcutaneous nodules (P<0.001). Reaction rates decreased with a longer dose interval between the first two doses. The peak anti-PA IgG antibody response of subjects given two doses of AVA 4 weeks apart IM or SQ was comparable to that seen among subjects who received three doses of AVA at 2-week intervals. The IM route of administering this aluminum hydroxide adsorbed vaccine is safe and has comparable peak anti-PA IgG antibody levels when two doses are administered 4 weeks apart compared to the licensed initial dose schedule of three doses administered 2 weeks apart. A large pivotal study is being planned by the Centers for Disease Control and Prevention to confirm these results.

Immunogenicity of an inactivated Rift Valley fever vaccine in humans : a 12-year experience

Rift Valley fever (RVF) virus causes serious and fatal disease in animals and man. To protect personnel who work with RVF virus in the laboratory, or troops who may be exposed to this virus, the US Army successfully developed an improved version of inactivated RVF vaccine, TSI-GSD-200. From early 1986 to late 1997, 598 at-risk workers at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) were vaccinated as part of an occupational safety and health program. The subjects of this study received three subcutaneous doses (0, 7 and 28 days) of 0.5 ml of TSI-GSD-200. A total of 540 vaccinees (90.3%) initially responded (group A) with an 80% plaque-reduction neutralization antibody titer (PRNT80) of > or =1:40; whereas 58 subjects (9.7%) were initial nonresponders (group B) failing to achieve this titer. Volunteers who either failed to respond or who achieved a titer of > or =1:40 but whose titer waned below 1:40 were boosted 1-4 times with the same vaccine. Among 247 group A subjects who received the first recall injection, 242 (98%) were successfully boosted, achieving a PRNT80 > or =1:40. Thirty-three of 44 (75%) initial nonresponders were converted to responder status after the first booster, which is a lower rate than that of group A (P < 0.001). After the primary series and the first booster, Kaplan-Meier analysis showed 50% probability of group A members maintaining a titer of > or =1:40 for approximately eight years; whereas group B had a 50% probability of maintaining a titer for only 204 days. Group A immune response rates to boosts 1-4 ranged from 87 to 100% with geometric mean titers (GMTs) ranging from 80 to 916. Boosts 1-4 immune response rates of group B volunteers ranged from 67 to 79% with GMTs ranging from 90 to 177. Minor side effects to TSI-GSD-200 were noted in 2.7% of all vaccinees after primaries and 3.5% of all vaccinees who had primaries and up to four boosters. We conclude that the use of TSI-GSD-200 is safe and provides good long-term immunity in humans when the primary series and one boost are administered.

Anthrax vaccine: short-term safety experience in humans

Bacillus anthracis is the major terrorist and biological warfare agent of concern to civilian and military medical planners. The licensed anthrax vaccine, adsorbed (AVA) is believed to be an effective prophylactic medical countermeasure against this threat. Our objective in this report was to expand the safety database for this vaccine by assessing data on self-reported, short-term safety of AVA during more than 25 years of use, measured by local and systemic adverse events temporally associated with the administration of AVA. A minority of AVA recipients reported systemic and injection site reactions. Females reported a higher incidence of injection site and systemic adverse events than males. Data show a difference in incidence of local reactions between lots. A prospective, randomized, placebo-controlled study to actively examine reactogenicity is needed to more completely define the extent and nature of reactions associated with receipt of AVA in humans as well as to confirm the gender lot differences in local reaction rates.

Aluminum-containing vaccine associated adverse events: role of route of administration and gender

Anthrax vaccine, adsorbed (AVA) is a vaccine containing aluminum hydroxide that is administered as six subcutaneous (s.q.) doses over 18 months. It is the only aluminum hydroxide licensed for s.q. administration. To optimize the vaccination schedule and route of administration, a prospective pilot study comparing the use of fewer doses administered intramuscularly (i.m.) as well as s.q. with the licensed schedule and route was performed. Data from that study on injection site reactions were extracted for this report. Erythema and induration occurred more commonly when the vaccine was administered s.q. compared to i.m. (P < 0.0001, P = 0.002, respectively). S.q. nodules were found only among the s.q. group (P < 0.0001). Erythema, induration and s.q. nodules were more common in women compared with men (P < 0.001) after the first s.q. dose of AVA dose. Reaction rates decreased when the interval between the first two doses of AVA was increased from 2 to 4 weeks.

Anthrax vaccine: increasing intervals between the first two doses enhances antibody response in humans

The influence of dosing interval on the human antibody response to anthrax vaccine adsorbed (AVA) was evaluated in two retrospective serological studies. In both studies, the interval between the first two doses was 2, 3 or 4 weeks. In the first study, banked sera were selected from 89 at-risk individuals at a mean time of 13 days after the second dose of vaccine. In the second study, banked sera were selected from 51 at-risk individuals at a mean time of 48 days following the first dose of AVA. In both studies, the geometric mean anti-protective antigen IgG antibody titer increased significantly as the interval between the two doses increased from 2 to 4 weeks (p=0.0005-0.029). In the first study, the seroconversion rate also increased as the interval between the first two doses increased (p=0. 0034). A prospective, randomized study has been completed and is being analyzed to confirm these findings.

Antibody response to a delayed booster dose of anthrax vaccine and botulinum toxoid

We evaluated the prevalence and concentration of serum antibodies 18-24 months after primary inoculation with anthrax and botulinum vaccines, and assessed the reactogenicity and immunogenicity of a significantly delayed booster dose of these vaccines. Five hundred and eight male active-duty military personnel received one, two or three inoculations with anthrax vaccine and/or botulinum toxoid in 1990/1991 in preparation for Operations Desert Shield/Desert Storm. Subjects were vaccinated with the licensed anthrax vaccine, adsorbed (AVA) and pentavalent (ABCDE) botulinum toxoid (PBT) BB-IND 3723. Anthrax protective antigen (PA) IgG antibody was measured in serum using an immunocapture enzyme-linked immunosorbent assay (ELISA). A mouse neutralization test was used to determine the titer of Clostridium botulinum type A antitoxin in serum samples. The prevalence of anti-PA IgG was 30% in individuals 18-24 months after priming with one, two or three doses of AVA. After boosting, 99% of volunteers had detectable anti-PA IgG; only two individuals failed to respond. The prevalence of antibodies against botulinum toxin type A was 28% 18-24 months after initial priming. Following boosting, 99% of volunteers had serum titers >0.02IU/ml, and 97% responded with titers > or =0.25IU/ml. Systemic reactions to booster vaccinations could not be specifically ascribed to one or the other vaccine, but were generally mild and of brief duration. Forty-five percent of volunteers reported one or more systemic reactions over the course of 7 days. Injection site reactions of any kind occurred in 25% of AVA recipients and in 16% of PBT recipients; persistence of local reactions beyond 7 days was infrequent. While the kinetics and durability of immune responses must be studied, these findings suggest that booster doses of anthrax vaccine and botulinum toxoid sufficient to stimulate a robust anamnestic response may be given at times distant from receipt of the primary inoculations.

US Military contributions to the global response to pandemic chikungunya

Chikungunya virus, transmitted by mosquitoes to man, causes an acute illness characterized by fever, rash and striking joint symptoms. US Military investigators developed, manufactured at The Salk Institute-Government Services Division (TSI-GSD), and tested the live, attenuated Chikungunya Vaccine TSI-GSD-218. The manufacturing facility stopped production in 1994. The Chikungunya Vaccine TSI-GSD-218 development effort was terminated in 1998, and materials were archived. In 2005, an alarming outbreak of chikungunya disease began in Africa and spread to islands in the Indian Ocean and throughout much of Asia. Abrupt epidemics with high attack rates and serious, even fatal, complications were reported, and travelers carried the virus to Europe and the Americas. In response to urgent requests, the US Military offered assistance by providing non-exclusive access to the previously stored vaccine production seed materials, bulk vaccine, regulatory documentation, and reports of previous clinical trials. Five companies requested technology transfers. This experience provides lessons about epidemiological unpredictability, preparedness, vaccine manufacturing, the potential global importance of vaccine seed materials and the advisability of a global strategic plan. Consideration should be given to banking of vaccine production seeds, cell substrates, and manufacturing instructions. In view of the manufacturability, attenuation, and immunogenicity of Chikungunya Vaccine TSI-GSD-218, authorities may wish to consider this product as a possible candidate itself, as a comparator vaccine to improve upon, as a seed for inactivated vaccine, or as a source of virus or antigen for neutralization assays or immunoassays.

Protective antigen and toxin neutralization antibody patterns in anthrax vaccinees undergoing serial plasmapheresis.

ABSTRACT Recipients of licensed anthrax vaccine (AVA; Biothrax) could serve as a source of hyperimmune plasma and immunoglobulin for therapy and prophylaxis. We measured serum antibodies during serial weekly to biweekly plasmapheresis in 38 individuals previously vaccinated with 4 to 27 doses of AVA. Immunoglobulin G (IgG) to protective antigen (PA) and toxin neutralization assay (TNA) antibody levels were highly correlated (r = 0.86930 and P < 0.0001 for anti-PA concentration versus TNA concentration). Significant decreases in antibody titer and concentration were observed over time when compared for the number of days from the last AVA injection (P < 0.0001 for both anti-PA and TNA concentration) and for the number of days from the first plasmapheresis (P = 0.0007 for anti-PA concentration and P = 0.0025 for TNA concentration). The rate of the decrease in total IgG concentration (half-life [t1/2] = 198.90 days after first plasmapheresis) was significantly less than the decrease in anti-PA IgG (t1/2 = 63.53 days) (P < 0.0001), indicating that the reduction in anti-PA IgG was more likely due to natural decay than plasmapheresis. The time since the last injection and the time after initial plasmapheresis are important elements in considering an optimal schedule for collecting anthrax hyperimmune plasma. Good correlation between IgG to PA and TNA antibodies suggests that the anti-PA enzyme-linked immunosorbent assay can be used as a high-throughput screen for functional immune reactivity in donor plasma units.

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.