Evaluation of interferences between dengue vaccine serotypes in a monkey model.

Interferences between different antigens in the same vaccine formulation have been reported for some vaccines (e.g., polio vaccines, live attenuated dengue vaccine candidates). We examined interferences between the four serotypes of ChimeriVax dengue vaccines (CYDs) in a monkey model when present within a tetravalent formulation in equal concentrations (TV-5555). Immunoassays of vaccinated non-human primates showed that serotype 4 (DEN-4), and to a lesser extent, DEN-1 were dominant in terms of neutralizing antibody levels. Parameters that affected the interferences were identified, including 1) the simultaneous administration of two complementary bivalent vaccines at separate anatomical sites drained by different lymph nodes; 2) the sequential administration of two complementary bivalent vaccines; 3) the establishment of heterologous flavivirus pre-immunity before subsequent tetravalent immunization; 4) the adaptation of formulations by decreasing the dose of the immunodominant serotype; and 5) the administration of a 1-year booster. The applicability of these data to human responses is discussed.

Cell-mediated immunity induced by chimeric tetravalent dengue vaccine in naive or flavivirus-primed subjects.

Three independent, phase 1 clinical trials were conducted in Australia and in USA to assess the safety and immunogenicity of sanofi pasteur dengue vaccine candidates. In this context, Dengue 1-4 and Yellow Fever 17D-204 (YF 17D)-specific CD4 and CD8 cellular responses induced by tetravalent chimeric dengue vaccines (CYD) were analyzed in flavivirus-naive or flavivirus-immune patients. Tetravalent CYD vaccine did not trigger detectable changes in serum pro-inflammatory cytokines, whatever the vaccinees immune status, while inducing significant YF 17D NS3-specific CD8 responses and dengue serotype-specific T helper responses. These responses were dominated by serotype 4 in naive individuals, but a booster vaccination (dose #2) performed 4 months following dose #1 broadened serotype-specific responses. A similar, broader response was seen after primary tetravalent immunization in subjects with pre-existing dengue 1 or 2 immunity caused by prior monovalent live-attenuated dengue vaccination. In all three trials, the profile of induced response was similar, whatever the subjects' immune status, i.e. an absence of Th2 response, and an IFN-gamma/TNF-alpha ratio dominated by IFN-gamma, for both CD4 and CD8 responses. Our results also showed an absence of cross-reactivity between YF 17D or Dengue NS3-specific CD8 responses, and allowed the identification of 3 new CD8 epitopes in the YF 17D NS3 antigen. These data are consistent with the previously demonstrated excellent safety of these dengue vaccines in flavivirus-naive and primed individuals.

Combined typhoid fever and hepatitis A vaccine: comparison of immunogenicity and safety to concomitant monovalent vaccine over 3 years.

BACKGROUND: The safety and immunogenicity of Viatim, a combined hepatitis A (HA) and typhoid fever (Vi) vaccine, were compared with the monovalent component vaccines up to and 1 month after a booster dose at 3 years. METHODS: Healthy, adult volunteers were randomized to receive Viatim (group A, n = 179) or separate HA and Vi vaccines (group B, n = 181); subgroups were boosted after 3 years with Viatim (groups C and D, n = 56 and 46, respectively). Local and systemic reactions were recorded for 28 days postvaccination. Seroconversion and seroprotection rates and geometric mean antibody concentrations were measured at 14 and 28 days, 1, 2, and 3 years postvaccination, and 28 days after the booster dose. RESULTS: Local and systemic safety profiles were equivalent between the two groups. Immediate local reactions were infrequent (1 in group A and 2 in group B). Local reactions, consisting mostly of mild or moderate pain, were least frequent with monovalent HA. Antibody concentrations to both antigens were similar in groups A and B, in which HA seroprotection rates (> or = 20 mIU/mL) were respectively, 98.7% and 100% at day 28, and 99.1% and 99.0% after 3 years, achieving 100% after the booster. Vi seroprotection rates (> or = 1 microg/mL) of 85.2% and 84.9% after 28 days fell to 32.1% and 35.6% after 3 years, increasing to 67.3% and 69.8% after the booster dose. CONCLUSIONS: The combined HA/Vi vaccine, Viatim, had equivalent tolerability and safety and was as rapidly immunogenic as its component monovalent vaccines when given concurrently. A booster dose after 3 years significantly increased antibody levels with some evidence of relative hyporesponsiveness of the typhoid response.

A randomized, open-label study of the immunogenicity and reactogenicity of three lots of a combined typhoid fever/hepatitis A vaccine in healthy adults.

BACKGROUND: Travelers are often advised to receive both the typhoid fever and hepatitis A virus (HAV) vaccines, particularly when going to areas where the 2 diseases are endemic. Thus, combined administration of these vaccines could make immunization more acceptable by reducing the number of injections needed. OBJECTIVE: This study compared the safety profiles and immunogenicity of 3 batches of a combined typhoid fever/HAV vaccine administered using a dual-chamber bypass syringe. METHODS: This randomized, open-label study was conducted at 2 university-based travel clinics in Germany and Austria. Subjects received a single IM injection from 1 of 3 batches of the combined vaccine. Blood samples were drawn immediately before and 28 days after vaccination to evaluate the response to the 2 antigens by assessing geometric mean titers (GMTs) and rates of seroconversion and seroprotection. Subjects recorded all adverse events (AEs) occurring during the study period in a diary. RESULTS: Six hundred ten healthy adults were enrolled in the study. Twenty-eight days after vaccination, 90.6% of the study population had protective typhoid Vi antibody titers (> or = 1 microg/mL) and 100% had protective HAV antibody titers (> or = 20 mIU/mL). Seroconversion rates and GMTs were not significantly different between the 3 batches. There were no differences with regard to local or systemic AEs between the 3 batches of vaccine. There were no immediate adverse reactions (within 30 minutes of vaccination) and no serious AEs related to vaccination. Of 609 evaluable subjects (1 was lost to follow-up after the first visit), 555 (91.1%) experienced > or = 1 local reaction within the first 7 days after vaccination, mainly pain at the injection site (550 [90.3%]), but only 26 (4.3%) described this pain as severe. Vaccine-related headache and mild to moderate asthenia were each reported by 54 subjects (8.9%). Symptoms resolved spontaneously in all cases. CONCLUSIONS: The 3 batches of the combined typhoid fever/HAV vaccine administered by dual-chamber bypass syringe were equally well tolerated and effective in healthy adults, and did not differ significantly in terms of GMTs or seroconversion rates.

Immunological priming of one dose of inactivated hepatitis A vaccine given during the first year of life in presence of maternal antibodies.

BACKGROUND: In hepatitis A virus (HAV)-seronegative infants, inactivated hepatitis A vaccines are highly immunogenic. On the contrary, in infants who are HAV-seropositive before vaccination, the interfering effect of passively-transferred maternal anti-HAV antibodies leads to lower post-primary immunization anti-HAV levels, as compared to those achieved by seronegative infants. One possible way to overcome this drawback is to delay hepatitis A vaccination later during the first year of life. The objective of the study was to document the immunogenicity of an inactivated hepatitis A vaccine in 6 months old HAV-seropositive infants, given as two dose regimen consisting of a single primary immunization at 6 months of age, followed by a booster dose 6 months later. METHODS: The immunogenicity of one hepatitis A vaccine (Avaxim pediatric, Aventis Pasteur) was documented in 108 6 months old, HAV-seropositive infants randomly assigned to receive one priming dose of hepatitis A vaccine either concomitantly with (Group 2) or 2 weeks after the third dose of routine diphteria-tetanus-whole cell pertussis reconstituting lyophilized tetanus conjugated Haemophilus influenzae type b (DTwcP//PRP approximately T) vaccine and oral poliomyelitis vaccine (OPV) (Group 1). A booster dose was given 6 months later, concomitantly with MMR vaccine. RESULTS: The 91 infants who were HAV-seropositive (ELISA titer >20 mIU/ml) at the moment of primo vaccination remained seropositive 1 month later. Geometric mean titers (GMT) decreased from 292 and 278 mIU/ml 1 month after the first dose, to 77.6 and 76.0 mIU/ml 6 months after, in Groups 1 and 2, respectively. Post-booster titers increased markedly in both groups, with GMTs of 1731 and 1866 mIU/ml and geometric mean post/pre-immunization titer ratios of 22.3 and 24.6, respectively. CONCLUSIONS: These results suggest that immunological priming induced by a single dose of Avaxim pediatric administered to 6 or 6.5 months old, HAV-seropositive infants is present and should not preclude the use of this vaccine in such populations.