Influenza Immunization in the Context of Preexisting Immunity

Abstract

Although we develop influenza immunity from an early age, it is insufficient to prevent future infection with antigenically novel strains. One proposed way to generate long-term protective immunity against a broad range of influenza virus strains is to boost responses to the conserved epitopes on the hemagglutinin, the major surface glycoprotein on the influenza virus. Influenza-specific humoral immunity comprises a large fraction of the overall immune memory in humans, and it has been long recognized that preexisting immunity to influenza shapes the response to subsequent influenza infections and vaccinations. However, the mechanisms by which preexisting immunity modulates the response to influenza vaccination are still not completely understood. Using a set of mathematical models, we explore several hypotheses that may contribute to diminished boosting of antibodies to conserved epitopes after repeated vaccinations.

Repeated influenza vaccination provides cumulative protection from distinct H3N2 viruses

“…The mouse model allowed us to study several immune parameters and determine protection from lethal viral challenge. The study of repeat vaccination in humans can be confounded by the immunocompetence of the vaccinee, diverse and unknown previous influenza immunisations and virulence and transmissibility of influenza virus strains 12,16,25 . Our study focused on the immune responses to repeated H3N2 exposure which has been circulating since 1968 and has evolved since then 26 .…”

Sex-specific effects of aging on the humoral immune response to repeat vaccination with the high-dose seasonal influenza vaccine in older adults

“…We recently reported a similar effect in younger adult healthcare workers, where mandatory vaccination policies result in exceptionally high rates of immunization 49 . While some argue that high levels of pre-existing antibodies interfere with the generation of de novo immune responses 24,27 , others suggest that ratio-based measures simply do not appropriately control for imbalances in levels of pre-existing humoral immunity 50 . Following the latter interpretation, a "ceiling effect" is evident in our data, whereby the limit of detection of the assay prohibits observing seroconversion or a large fold-rise in individuals with high levels of pre-existing humoral immunity.…”

“…According to immune imprinting theory, the memory response established by an individual's first influenza exposure has a lifelong effect on subsequent immune responses to infection or vaccination 22 . Broad preexisting immunity is thought to have negative consequences, as pre-existing antibodies can suppress the response to novel influenza virus strains by reducing the amount of available antigen or epitope masking 23,24 . A theoretical benefit of HD-IIV is that pre-existing antibodies cannot sequester the increased amount of antigen delivered, and, thus, more antigen is available to activate memory B cells and elicit a protective response [25][26][27] .…”

COVID-19 is not influenza

“…4 Only haemorrhagic strokes (and not other types of stroke) were more frequent among patients with COVID-19. The median length of stay in the ICU for COVID-19 was twice as long as for influenza (15 days [SD 14] vs 8 days [9]; p<0•0001). 4 Patients with COVID-19 were more often obese or overweight, diabetic, hypertensive, and dyslipidaemic, whereas patients with influenza more often had chronic heart failure, peripheral vascular disease, chronic respiratory disease, cirrhosis, and deficiency anaemia.…”

“…Therefore, it must be assumed that there was some residual immunity against influenza in the influenza cohort. 9 By contrast, severe acute respiratory syndrome coronavirus 2 is a new virus for which no one had any previous immunity. Therefore, the difference between the two disease groups could represent differences between people with some immunity compared with people with no immunity.…”