Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths

Abstract

Pathogen interference is the ability of one pathogen to alter the course and clinical outcomes of infection by another. With up to 3000 species of human pathogens the potential combinations are vast. These combinations operate within further immune complexity induced by infection with multiple persistent pathogens, and by the role which the human microbiome plays in maintaining health, immune function, and resistance to infection. All the above are further complicated by malnutrition in children and the elderly. Influenza vaccination offers a measure of protection for elderly individuals subsequently infected with influenza. However, all vaccines induce both specific and non-specific effects. The specific effects involve stimulation of humoral and cellular immunity, while the nonspecific effects are far more nuanced including changes in gene expression patterns and production of small RNAs which contribute to pathogen interference. Little is known about the outcomes of vaccinated elderly not subsequently infected with influenza but infected with multiple other non-influenza winter pathogens. In this review we propose that in certain years the specific antigen mix in the seasonal influenza vaccine inadvertently increases the risk of infection from other non-influenza pathogens. The possibility that vaccination could upset the pathogen balance, and that the timing of vaccination relative to the pathogen balance was critical to success, was proposed in 2010 but was seemingly ignored. Persons vaccinated early in the winter are more likely to experience higher pathogen interference. Implications to the estimation of vaccine effectiveness and influenza deaths are discussed.

Effect of Age, Sex, and COVID-19 Vaccination History on All-Cause Mortality: Unexpected Outcomes in a Complex Biological and Social System

“…A review of pathogen interference strongly implied that the efficacy of vaccination should generally vary over time, i.e., month of vaccination [4,33]. This is because COVID-19 infection and COVID-19 vaccination are competing with other human pathogens whose incidence varies with time and place, and in response to COVID-19 infection [4,33].…”

“…There is increasing awareness that vaccines exhibit both specific and non-specific effects [1][2][3][4].The specific effects are measured by the efficacy of the vaccine against the targeted pathogen, while the non-specific effects can be discerned by evaluating the change in all-cause mortality. A fully efficacious vaccine will reduce deaths arising from the targeted pathogen and will thereby also reduce all-cause mortality .…”

“…antitumor effects [12], and the ability of pathogen antigens to initiate the mechanisms of pathogen interference, which are mediated by the production of small noncoding RNAs (miRNAs) [4]. The small non-coding RNAs (ncRNAs): miRNA, siRNA etc.…”

“…The small non-coding RNAs (ncRNAs): miRNA, siRNA etc. [4]. The small ncRNAs then regulate gene expression which either enhances or diminishes infection by other pathogens.…”

“…The small ncRNAs then regulate gene expression which either enhances or diminishes infection by other pathogens. Vaccines (as a class of antigens) also stimulate the production of miRNAs [4], and hence create sometimes unexpected, nonspecific outcomes like pathogen interference. Vaccination may also induce antibody-dependent enhancement with negative health consequences [13][14][15][16].…”