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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]

Preventive viral vaccine efficacy trials require large-scale sample analysis to quantitate immune responses and their correlation with infection outcomes. Traditional plaque reduction assays measure a functionally important form of humoral immunity, neutralizing antibody titer. These assays, however, are time-consuming and laborious. We previously developed a higher throughput assay of neutralizing antibody to herpes simplex viruses 1 and 2 (Blevins et al., PLOS ONE, 10(12), e0144738) using the enzyme-linked virus inducible system (ELVIS) cell line; this cell line produces β-galactosidase in response to HSV infection. Here, serum samples from recipients of an investigational vaccine in the Herpevac Trial for Women were used to compare the ELVIS cell assay with the lower throughput, traditional plaque reduction assay. We demonstrate that neutralizing antibody titers to HSV-1 or HSV-2 determined using ELVIS cells positively correlate with neutralizing antibody titers determined by traditional plaque reduction assay, thus validating a higher throughput alternative for large-scale sample analysis. [ABSTRACT FROM AUTHOR]

The Herpevac Trial for Women revealed that three dose HSV-2 gD vaccine was 58% protective against culture-positive HSV-1 genital disease, but it was not protective against HSV-2 infection or disease. To determine whether vaccine-induced immune responses had selected for a particular gD sequence in strains infecting vaccine recipients compared with viruses infecting control subjects, genetic sequencing studies were carried out on viruses isolated from subjects infected with HSV-1 or HSV-2. We identified naturally occurring variants among the gD sequences obtained from 83 infected subjects. Unique or low frequency amino acid substitutions in the ectodomain of gD were found in 6 of 39 HSV-1-infected subjects and in 7 of 44 HSV-2-infected subjects. However, no consistent amino acid change was identified in isolates from gD-2 vaccine recipients compared with infected placebo recipients. gC and gE surround and partially shield gD from neutralizing antibody, and gB also participates closely in the viral entry process. Therefore, these genes were sequenced from a number of isolates to assess whether sequence variation may alter protein conformation and influence the virus strain’s capacity to be neutralized by vaccine-induced antibody. gC and gE genes sequenced from HSV-1-infected subjects showed more variability than their HSV-2 counterparts. The gB sequences of HSV-1 oral isolates resembled each other more than they did gB sequences rom genital isolates. Overall, however, comparison of glycoprotein sequences of viral isolates obtained from infected subjects did not reveal any singular selective pressure on the viral cell attachment protein or surrounding glycoproteins due to administration of gD-2 vaccine. [ABSTRACT FROM AUTHOR]

Although a cure for HCV is on the near horizon, emerging drug cocktails will be expensive, associated with side-effects and resistance making a global vaccine an urgent priority given the estimated high incidence of infection around the world. Due to the highly heterogeneous nature of HCV, an effective HCV vaccine which could elicit broadly cross-neutralizing antibodies has represented a major challenge. In this study, we tested for the presence of cross-neutralizing antibodies in human volunteers who were immunized with recombinant glycoproteins gpE1/gpE2 derived from a single HCV strain (HCV1 of genotype 1a). Cross neutralization was tested in Huh-7.5 human hepatoma cell cultures using infectious recombinant HCV (HCVcc) expressing structural proteins of heterologous HCV strains from all known major genotypes, 1–7. Vaccination induced significant neutralizing antibodies against heterologous HCV genotype 1a virus which represents the most common genotype in North America. Of the 16 vaccinees tested, 3 were selected on the basis of strong 1a virus neutralization for testing of broad cross-neutralizing responses. At least 1 vaccinee was shown to elicit broad cross-neutralization against all HCV genotypes. Although observed in only a minority of vaccinees, our results prove the key concept that a vaccine derived from a single strain of HCV can elicit broad cross-neutralizing antibodies against all known major genotypes of HCV and provide considerable encouragement for the further development of a human vaccine against this common, global pathogen. [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]

Background: We conducted a double-blind, randomized trial of three dilutions of vaccinia virus vaccine in previously unimmunized adults in order to assess the clinical success rates, humoral responses, and virus-specific activity of cytotoxic T cells and interferon-γ–producing T cells. Methods: Sixty healthy adults were inoculated intradermally by bifurcated needle with undiluted vaccine (dose, 107.8 plaque-forming units [pfu] per milliliter), a 1:10 dilution (dose, 106.5 pfu per milliliter), or a 1:100 dilution (dose, 105.0 pfu per milliliter); there were 20 subjects in each group. The subjects were monitored with respect to vesicle formation (an indicator of successful vaccination), the viral titer at the time of peak lesion formation, antiviral antibodies, and cellular immune responses. Results: A vaccinia vesicle developed in 19 of the 20 subjects who received undiluted vaccine (95 percent), 14 of the 20 who received the 1:10 dilution (70 percent), and 3 of the 20 who received the 1:100 dilution (15 percent). One month after vaccination, 34 of 36 subjects with vesicles had antibody responses, as compared with only 1 of 24 subjects without clinical evidence of vaccinia virus replication. Vigorous cytotoxic T-cell and interferon-γ responses occurred in 94 percent of subjects with vesicles, and a cytotoxic T-cell response occurred in only one subject without a vesicle. Conclusions: The vaccinia virus vaccine (which was produced in 1982 or earlier) still has substantial potency when administered by a bifurcated needle to previously unvaccinated adults. Diluting the vaccine reduces the rate of successful vaccination. The development of vesicular skin lesions after vaccination correlates with the induction of the antibody and T-cell responses that are considered essential for clearing vaccinia virus infections. (N Engl J Med 2002;346:1275-80.) [ABSTRACT FROM AUTHOR]