Vaccination of newborn monkeys with an influenza HA stem nanoparticle adjuvanted with R848 and AddaVax results in broadened HA recognition and increased antibody secreting cells to HA stem following H1N1 challenge.

BACKGROUND

How infection shapes recall responses in the setting of preexisting influenza virus hemagglutinin (HA) stem-focused immunity has important implications given the known impact of imprinting on future immune responses. Adoption of an HA-based universal stem vaccine approach for young infants would likely result in stem-specific imprinting. Understanding how imprinting programs memory B cell recall and early antibody responses to HA stem and head in newborns is therefore essential.

METHODS

African green monkeys vaccinated with a A/New Caledonia/20/1999 (NC99) hemagglutinin stem-bearing nanoparticle (H1ssF) adjuvanted with R848+AddaVax as newborns were challenged with H1N1 A/California/07/2009 (Ca09). Antibody and draining lymph node cellular responses were analyzed on d7 following challenge. Both quantitative and qualitative aspects of the antibody response were assessed.

RESULTS

Our previous studies showed newborn African green monkeys vaccinated with an R848+AddaVax dual adjuvanted H1ssF nanoparticle exhibited a robust stem-specific antibody response that had broad reactivity and enhanced functional activity. In the present study, we investigated how the response elicited by this vaccine was recalled following infection, evaluating both antibody and cellular responses. While challenge resulted in increases in recognition of many heterologous HA molecules, not all responses showed evidence of boosting at this timepoint. Control (Ctrl) animals had limited neutralizing activity to Ca09 at d7 following infection, whereas challenge resulted in significant increases in neutralizing antibody to the challenge virus. Compared to Ctrl animals, vaccinated infants exhibited lower germinal center B cell responses and IFNγ-producing T follicular helper (Tfh) responses. However, vaccinated infants exhibited a significant increase in HA stem-specific plasmablasts and plasma cells in the lung-draining tracheobronchial lymph nodes together with similar head-specific responses.

CONCLUSION

Collectively, these findings are consistent with efficient recall of stem-specific responses generated by vaccination with dual adjuvanted H1ssF administered to newborn African green monkeys in response to influenza virus challenge. Interestingly, challenge with the heterologous virus appears to reshape the reactivity profile of the stem-specific response. Further, vaccinated animals exhibit robust early antibody-secreting cell responses, including increased numbers of stem-specific cells, without an apparent reduction in the generation of head-specific cells.