Influenza Preimmunity Increases Vaccination Efficacy by Influencing Antibody Longevity, Neutralization Activity, and Epitope Specificity

Abstract

Influenza virus infections are a recurrent public health problem despite vaccination efforts. The well known yearly cycling of influenza viruses is the result of the reciprocal relationship between the host and virus. From frequent infections and yearly vaccinations, humans build a complex immune history but very little is known about vaccine responses in the imprinted (preimmune) host. To investigate the preimmune host immune responses to split-virion vaccination, we imprinted ferrets with a sublethal dose of the historical seasonal H1N1 strain A/USSR/90/1977 (USSR/77) for subsequent vaccination. A +60 day recovery period was given to build immune memory prior to vaccination with a split virion QIV vaccine. To evaluate protection, the ferrets were challenged with a 2009 H1N1 pandemic virus matching the vaccine antigens. The preimmune-vaccinated ferrets did not experience significant disease during challenge while the naïve-vaccinated group had severe disease. Hemagglutination inhibition (HAI) assays showed that preimmune ferrets had a faster and longer antibody response post vaccination for all vaccine antigens. To investigate the immune mechanisms leading to disease protection, we performed microneutralization and isotype ELISA assays. After vaccination preimmune ferrets developed antibodies that were more functional for virus neutralization with the dominant isotype being IgG, suggesting B cell maturity and plasticity in a pre-existing B cell. These results showed the preimmune host had greater responses to vaccination, and the predominant IgG virus specific antibodies suggested a flexible long-lived B cell response which can be manipulated at vaccination. These results are important and should be considered for vaccine design.

Funding Statement: This work was supported by research is funded by the National Institutes of Health NIH 1U01AI11598-01 Subaward no. F8802-16 S and National Institutes of Health NIH Contract HHSN272201000031I, Order Number HHSN27200003, Task A88 AAK and TMR.

Declaration of Interests: The authors state that they "have no relationships to declare."

Ethics Approval Statement: All animal work was conducted in strict accordance with the Canadian Council of Animal Care (CCAC) guidelines. The protocol license numbers AUP 5316 and 1031 were assigned by the Animal Care Committee of the University Health Network (UHN). UHN has certification with the Animals for Research Act, including for the Ontario Ministry of Agriculture, Food and Rural Affairs, Permit Numbers: #0132-01 and #0132-05, and follows NIH guidelines (OLAW #A5408-01). The animal use protocol was approved by the UHN Animal Care Committee (ACC).

Keywords: Influenza virus; Vaccine; Haemagglutinin; Split-Virion; antibody; Isotype; Virus neutralization