Background Herpes simplex virus 2 (HSV2) causes genital herpes in >400 million persons worldwide. Methods We conducted a randomized, double-blinded, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults were enrolled in each of 3 serogroups of individuals: those negative for both HSV1 and HSV2 (HSV1−/HSV2−), those positive or negative for HSV1 and positive for HSV2 (HSV1±/HSV2+), and those positive for HSV1 and negative for HSV2 (HSV1+/HSV2−). Sixty participants received vaccine or placebo at 0, 1, and 6 months. The primary end point was the frequency of solicited local and systemic reactions to vaccination. Results Eighty-nine percent of vaccinees experienced mild-to-moderate solicited injection site reactions, compared with 47% of placebo recipients (95% confidence interval [CI], 12.9%–67.6%; P = .006). Sixty-four percent of vaccinees experienced systemic reactions, compared with 53% of placebo recipients (95% CI, −17.9% to 40.2%; P = .44). Seventy-eight percent of HSV1−/HSV2− vaccine recipients had a ≥4-fold increase in neutralizing antibody titer after 3 doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36%, 46%, and 27% of HSV1−/HSV2−, HSV1±/HSV2+, and HSV1+/HSV2− participants, respectively, 1 month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants, respectively. Conclusions HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV-seronegative vaccinees. Clinical Trials Registration NCT01915212.

Background It is imperative to identify new targets for improved vaccines and therapeutics against influenza and one such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein. Methods We conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. A single 50mg/kg dose of CR6261 was infused 24 hours after challenge and the primary efficacy outcome was area under the curve of viral RNA detection over time. Results Ninety-one healthy volunteers were randomized and underwent influenza challenge; 49 received CR6261 and 42 placebo. CR6261 had no statistically significant effect on AUC (AUC 48.56 log (copies/mL) x days, IQR 202 vs. AUC 25.53 log (copies/mL) x days, IQR 155), P=0.315), and no clinically significant effect on influenza disease measures including number of symptoms, duration of symptoms, or FLU-PRO scores. Preexisting anti-NA antibody titers were most predictive of reduced influenza disease. CR6261 reached a mean peak serum concentration of 1x10 6 ng/ml 15 minutes after infusion, and a mean peak of 5.97x10 2 ng/ml in the nasal mucosa 2-3 days after infusion. Conclusions The results of this study suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may be limited in efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic.

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