Valkenburg REINVIGORATE NIH
Project summary
Older adults experience the greatest burden of respiratory virus infections, especially influenza
viruses. Older adults are recommended for annual influenza vaccination due the high
morbidity in this age group, yet underperformance of standard inactivated vaccines has led to
the recommendation of enhanced vaccines, which include high dose, HA only or adjuvanted
formulations to improve immunogenicity. However, there is still no consensus on preferred
formulation in older adults despite their recommendation, and up to 80% of older adults fail to
seroconvert after vaccination. Age impacts the ability to prime new immune responses to
antigenic drift variants of influenza viruses, due to reduced immune functions and competition
of existing responses for subtle changes in new vaccine strains, which is compounded by
annual vaccination. Here, in this study we plan to leverage our completed 4-year randomised
control trial in older adults of standard versus enhanced influenza vaccines, to determine the
combination and longitudinal repeated effect of vaccination on the antibody and cellular
response. Our initial studies have found adjuvanted vaccines increase total T follicular helper
cells increasing the magnitude, avidity, and cross-reactivity of the antibody response.
Therefore, we plan to use mutational profiling of influenza viruses grown in the presence of
vaccine serum across different conditions to assess the antigenic focussing and mutational
pressure generated. The quality of antibody responses will be assessed in multiplex
approaches. Whilst cytokine producing T cell responses are minimally boosted by inactivated
vaccines, we found a year 1 advantage of adjuvanted vaccines for CD8+ T cells which was
diminished by year 4 of the study. High dimensional flow cytometry, antigen specific probes
for T and B cells, and in vitro stimulation will be used to characterise the phenotype and
function of innate and adaptive cellular responses, including repertoire shaped by repeat
vaccination. Innate, T and B cell responses will be assessed at the molecular level by
repertoire analysis, and transcriptional activity by 10X scRNAseq, with a focus on participants
that fail to seroconvert by standard HAI antibodies as their T cell responses come to the fore.
Ultimately, this study will provide rationale for vaccine use in older adults and universal vaccine
development for broadly cross-reactive immunity.
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