Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models
Sita Awasthi, … , Gary H. Cohen, Harvey M. Friedman
Sita Awasthi, … , Gary H. Cohen, Harvey M. Friedman
Published October 7, 2021
Citation Information: J Clin Invest. 2021;131(23):e152310. https://doi.org/10.1172/JCI152310.
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Research Article Infectious disease

Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models

Abstract

Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic, latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins, with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing-antibody titers were higher at 1 month and declined far less by 8 months in mRNA- compared with protein-immunized animals. Both vaccines protected against death and genital lesions when infected 1 month after immunization; however, protection was more durable in the mRNA group compared with the protein group when infected after 8 months, an interval representing greater than 15% of the animal’s lifespan. Serum and vaginal neutralizing-antibody titers correlated with protection against infection, as measured by genital lesions and vaginal virus titers 2 days after infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times after immunization that persisted for up to 1 year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.

Authors

Sita Awasthi, James J. Knox, Angela Desmond, Mohamad-Gabriel Alameh, Brian T. Gaudette, John M. Lubinski, Alexis Naughton, Lauren M. Hook, Kevin P. Egan, Ying K. Tam, Norbert Pardi, David Allman, Eline T. Luning Prak, Michael P. Cancro, Drew Weissman, Gary H. Cohen, Harvey M. Friedman

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Figure 2

Enhanced efficacy of mRNA compared with protein vaccine in guinea pigs.

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Enhanced efficacy of mRNA compared with protein vaccine in guinea pigs. ...
(A) Survival. P values compare groups with 100% survival with protein at 8 months or naive. (B) Percentage days with genital disease. Actual number of days with genital disease shown above graph. (C) Days with urinary retention measured on days 1–20 after infection. (D) Weight loss: P = 0.1064 comparing naive and protein at 8 months; P = 0.0038 comparing mRNA and protein at 8 months; P = 0.0029 comparing protein at 1 and 8 months; P = 0.0205 comparing mRNA at 1 and 8 months. (E and F) Day 2 and day 4 vaginal virus titers after infection. (G) Vaginal shedding of HSV-2 DNA days 28 to 48 after infection. Numbers above the data points represent the number of days HSV-2 shedding was detected (numerator) and the total number of days sampled (denominator). Numbers below the data points represent the number of days replication-competent virus was isolated (numerator) and the total number of days of HSV-2 DNA shedding (denominator). The green symbol represents an HSV-2 DNA sample with replication-competent virus. n = 10/group for naive and protein at 1 month and 8 months, n = 20/group for mRNA at 1 month and 8 months. P values were calculated by log-rank test (A), Kruskal-Wallis test with Dunn’s correction for multiple comparisons (B, C, E, and F), Mann-Whitney-Wilcoxon test with Holm’s adjustment for multiple comparisons (D), or 2-tailed Fisher’s exact test for numbers above or below graphs in B and G.