Discussion
virus infection, inflammation, infection, lupus, HSV2, HSV2 vaccine, yellow fever, RTS
VIRUS, VIRUS INFECTION, MALARIA, INFLAMMATION, DISEASE, VIRAL INFECTION, INFECTION, LUPUS, YELLOW FEVER, INFLUENZA
To understand the interaction between sex and prior exposure in the context of an immune response in vivo, we studied the response to a replication-defective HSV2 vaccine in persons with different prior exposure to HSV. We used a systems immunology approach characterizing peripheral blood transcriptomic and cell population phenotypes. While prior studies using systems approaches have been reported for live attenuated virus, subunit, and vectored vaccines, this is the first such study of a replication-defective vaccine in humans. After a longitudinal analysis throughout the three-dose vaccine regimen, we focused on transcriptional responses at day 1 after the first dose, as these exhibited the most robust changes associated with both sex and prior exposure. Changes in these phenotypes were determined and comparisons were made with other outcomes, such as the observation of more robust vaccination responses in women than men in subjects previously naive to HSV, revealed by faster neutralizing antibody responses. Thus, we provide insights for how prior exposure and sex interact to shape the early innate immune response.The day 1 transcriptional responses differed between HSV529 vaccine recipients based on prior exposure to HSV. Responses to HSV529 by HSV seronegative individuals overlapped strongly with those previously reported for recipients of the yellow fever vaccine, whereas responses to HSV529 by HSV seropositive individuals were significantly different from those who were HSV seronegative and instead overlapped with persons who had been vaccinated with influenza. These findings support the notion that prior exposure to the pathogen against which the vaccine is targeting is a major determinant of the early innate immune response to the vaccine, independent of the vaccine type (live attenuated, subunit, or replication-defective) or the pathogen itself (yellow fever virus, influenza virus, or HSV).Interestingly, IFN responses appeared to be skewed toward IFN-α in the HSV seronegative vaccine recipients but toward IFN-γ in the HSV seropositive group. Type I IFNs, including IFN-α, are produced very early after viral infections, including with HSV, and cellular RNA and DNA sensors for HSV produce type I IFNs in response to virus infection (Sex was associated with day 1 transcriptional responses, but the enriched pathways differed between HSV naive and seropositive individuals. A transcriptional profile of increased responses was observed for women, specifically for those previously naive to HSV. The transcriptomic modules and leading-edge genes that characterized this response were centered on type I IFN and antiviral pathways. This suggests that in the absence of prior exposure, the more robust transcriptional responses in women to a replication-defective virus may be due to an underlying difference in baseline inflammation or in the speed of induction of inflammation in comparison to men. Such IFN-associated broad immune activation has recently been found to underlie shared set point signatures for increased vaccine responsiveness in healthy individuals of both sexes (although this signature tends to be more elevated in females than males at baseline), as well as disease activity in patients with lupus (Despite the IFN response on day 1 that was associated with reduced antibody titers in HSV naive women, these individuals as a group showed the most robust antibody responses to HSV529, with more rapid antibody responses compared to HSV naive men. Overall, HSV naive individuals showed greater titer increases compared to HSV exposed subjects particularly at later timepoints. The diminished responses by HSV exposed subjects may also have resulted from suppression of HSV529 infection, in this case by preexisting neutralizing antibody or T cell immunity. This is supported by the large number of genes upregulated on day 1 after vaccination in HSV1More robust responses by women compared to men have been described for several vaccines (Prior studies suggest that HSV2 subunit vaccines are more effective in women than men (Due to the more rapid vaccine response in seronegative women observed in this study, we analyzed changes in plasmablasts. In a trial of the malaria recombinant protein vaccine RTS,S, increased plasmablasts were observed on day 1, but only after the second and third doses of vaccine (Several individual genes were highlighted by our transcriptomic screen. TLR7 is an X-linked gene for which higher levels of expression have been reported in B cells of naive female versus male mice after vaccination with inactivated influenza vaccine, and these higher levels of TLR7 correlated with high levels of antibodies in the female mice (Overall, our study confirms and adds to the substantial effects observed for prior exposure and sex in innate immune responses. We document at a systems level how these two variables interact in the context of response to a replication-defective vaccine, and determine resulting transcriptional response profiles that may form the basis for differences in neutralizing antibody responses in vivo. To improve vaccination effectiveness, it will thus be important to better understand how prior exposure and sex affect the innate responses that are increasingly being shown to shape subsequent adaptive immunity.