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Background: The glycoprotein D (gD)/AS04 vaccine failed to prevent herpes simplex virus (HSV) 2 in clinical trials. Failure was recapitulated in mice, in which the vaccine elicited neutralizing antibody but not antibody-dependent cell-mediated cytotoxicity (ADCC) responses. Preclinical findings suggest that ADCC is important for protection, but the clinical data are limited. We hypothesized that gD/AS04 and acute HSV-2 infection elicit primarily neutralizing antibodies, whereas ADCC emerges over time.Methods: HSV-specific immunoglobulin G, subclass, function (neutralization, C1q binding and ADCC), and antigenic targets were compared (paired t test or Mann-Whitney U test) at enrollment and after gD/AS04 vaccination, before and after HSV-2 acquisition in vaccine controls, and in an independent cohort with chronic HSV-2 infection.Results: Vaccination elicited only a neutralizing antibody response, whereas acute infection elicited neutralizing and C1q-binding antibodies but not a significant ADCC response. Antibodies to gD were exclusively immunoglobulin G1 and only neutralizing. In contrast, women with chronic HSV-2 infection had significantly greater ADCC responses and targeted a broader range of viral antigens compared with acutely infected or gD/AS04 vaccine recipients (P < .001).Conclusions: Results from gD/AS04 vaccinated or acutely infected women recapitulate murine findings of limited functional antibody responses, supporting the speculation that vaccines that generate polyfunctional and specifically ADCC responses may be required to prevent HSV-2 acquisition and limit recurrences. [ABSTRACT FROM AUTHOR]

Background. Influenza A H5N1 viruses pose a significant threat to human health. Methods. We conducted a multicenter, randomized, double-blind study in 394 healthy adults. Subjects were randomly assigned to receive 2 intramuscular doses of either saline placebo; influenza A/Vietnam! I 203/2004(H5N1) vaccine alone at 45, 30, or 15 µg per dose; vaccine at 15 or 7.5 µg per dose with MF59; or vaccine at 30, 15, or 7.5 µg per dose with aluminum hydroxide. Subjects were followed up for safety and blood samples were obtained to deter- mine antibody responses. Results. The vaccine formulations were well tolerated but local adverse effects were common; the incidence of these effects increased in a dose-dependent manner and was increased by the addition of adjuvants. The addition of MF59 increased the antibody response, whereas the addition of aluminum hydroxide did not. The highest antibody responses were seen in the group that received 15 µg of vaccine per dose with MF59, in which 63% of subjects achieved the predetermined endpoint (hemagglutination-inhibition titer ⩾40) 28 days after the second dose, compared with 29% in the group that received the highest dose (45 jµg per dose) of vaccine alone. Conclusions. A 2-dose regimen of subvirion influenza A (H5N1) vaccine was well tolerated. The antibody re- sponses to 15 µg of A/H5 vaccine with MF59 were higher than the responses to 45 µg of vaccine alone. [ABSTRACT FROM AUTHOR]

Background. Recombination technology can be used to create live attenuated respiratory syncytial virus (RSV) vaccines that contain combinations of known attenuating mutations. Methods. Two live attenuated, recombinantly derived RSV vaccine candidates, rA2cp248/404ΔSH and rA2cp248/404/1030ΔSH, were evaluated in 31 adults and in 95 children ≥6 months old. rA2cp248/404/1030ΔSH was subsequently evaluated in 44 infants 1–2 months old. These vaccine candidates share 4 attenuating genetic elements and differ only in a missense mutation (1030) in the polymerase gene. Results. Both vaccines were highly attenuated in adults and RSV-seropositive children and were well tolerated and immunogenic in RSV-seronegative children. Compared with that of rA2cp248/404ΔSH, replication of rA2cp248/404/1030ΔSH was restricted in RSV-seronegative children (mean peak titer, 104.3 vs. 102.5 plaque-forming units [pfu]/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/1030ΔSH was well tolerated in infants, only 44% of infants who received two 105.3-pfu doses of vaccine had detectable antibody responses. However, replication after administration of the second dose was highly restricted, indicating that protective immunity was induced. At least 4 of 5 attenuating genetic elements were retained in recovered vaccine viruses. Conclusions. rA2cp248/404/1030ΔSH is the first RSV vaccine candidate to be sufficiently attenuated in young infants. Additional studies are needed to determine whether rA2cp248/404/1030ΔSH can induce protective immunity against wild-type RSV. [ABSTRACT FROM AUTHOR]

We evaluated a combination respiratory syncytial virus (RSV) and parainfluenza 3 virus (PIV3) live, attenuated intranasal vaccine for safety, viral replication, and immunogenicity in doubly seronegative children 6-18 months old. RSV cpts-248/404 and PW3-cp4S vaccines were combined in a dose of 105 plaque-forming units of each per 0.5-mL dose and compared with monovalent vaccines or placebo. The virus shedding pattern of RSV was not different between monovalent RSV cpts-2481404 vaccine and combination vaccine. Modest reductions in the shedding of PIV3-cp45 vaccine virus were found after the administration of RSV cpts-2481404 and PIV3-cp45 vaccine, relative to monovalent PIV3 vaccine; 16 (76%) of 21 children given combination vaccine shed PIV3- cp45 versus 11 (92%) of 12 of those given monovalent PIV3 vaccine. Both vaccines were immunogenic, and antibody responses were similar between the monovalent groups and the combination group. Combined RSV/PV3 vaccine is feasible for simultaneous administration, and further studies are warranted. [ABSTRACT FROM AUTHOR]

A phase 2 evaluation of live attenuated parainfluenza type 3 (PIV3)­cold passage mutant 45 (cp45) vaccine was conducted in 380 children 6–18 months old; 226 children (59%) were seronegative for PIV3. Of the 226 seronegative children, 114 received PIV3-cp45 vaccine, and 112 received placebo. No significant difference in the occurrence of adverse events (i.e., runny nose, cough, or temperature ≤38 °C) was noted during the 14 days after vaccination. There was no difference between groups in the occurrence of acute otitis media or serous otitis media. Paired serum samples were available for 109 of the seronegative vaccine recipients and for 110 of the seronegative placebo recipients; 84% of seronegative vaccine recipients developed a ≥4-fold increase in antibody titers. The geometric mean antibody titer after vaccination was 1:25 in the vaccine group and <1:4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase 3 field trial. [ABSTRACT FROM AUTHOR]

Background Demonstration of protection by a M2SR (M2 deficient Single Replication) monovalent H3N2 vaccine was assessed in a phase 2a clinical trial in which the challenge virus was substantially drifted from the vaccine. M2SR is an investigational, live virus vaccine containing hemagglutinin (HA) and neuraminidase (NA) selected from targeted Type A influenza strains. M2SR undergoes only a single round of infection in the respiratory epithelium but evokes an immune response profile similar to wild-type influenza virus and protects ferrets against both homologous and heterologous influenza variants. Methods A blinded, randomized, placebo-controlled human challenge study (EudraCT #: 2017-004971-30) was conducted with M2SR containing HA and NA from A/Brisbane/10/2007 (H3N2). 18–55-year-old subjects received 1 IN dose of saline or 108 TCID50 of vaccine. 4 weeks later, 99 subjects were challenged IN with 106 TCID50 H3N2 A/Belgium/4217/2015 (Figures 1 and 2). Results Adverse events (AE) were similar between placebo (N = 51) and M2SR recipients (N = 48) during the 28 days after immunization. After challenge with A/Belgium/4217/2015, 35% of M2SR recipients experienced influenza infection and illness, compared with 49% of placebo subjects (Figure 3). An 18% reduction in viral load was noted after challenge for M2SR subjects. Serum microneutralization response to vaccine was detected in 54% of M2SR subjects (vs. 0/51 placebo subjects), and among these subjects a 34% reduction in viral load and 51% reduction in symptom scores was noted after challenge vs placebo. Among the 29% of subjects with post-vaccine response to both vaccine and challenge strains, a 62% reduction in viral load and 56% reduction in symptom scores was noted after challenge with highly drifted H3N2 (Figure 4). Conclusion One dose of M2SR protected healthy adults against influenza infection and illness with a highly drifted challenge strain. This is believed to be the first study to demonstrate protection against challenge with an influenza strain substantially different from the vaccine and indicates potential for improved breadth of protection by M2SR compared with current vaccines. The mild vaccine AE profile supports clinical trials of additional dose levels and regimens to enhance drifted strain protection by M2SR. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]