Immunogenicity response to the vaccine is a complicated process, which is affected by many factors, including vaccine and host factors.6, 14 In this study, we identified several factors associated with the responsiveness to the influenza vaccine. The Chi-square test, multivariable logistic regression analysis, and sum-rank test showed that vaccination history, chronic condition, age, and frequency of colds were important factors affecting immunogenicity responsiveness to the influenza vaccine. These results will help optimize influenza vaccination strategies and improve the effectiveness of the vaccine in humans.
In this study, participants with a vaccination history presented worse immunogenicity responsiveness to the influenza vaccines, indicating that continuous annual vaccination may lead to reduced vaccine efficacy, consistent with previous studies. A study evaluating the immunogenicity of trivalent inactivated influenza vaccine showed that the odds of seroconversion were strongly related to the baseline antibody titer, and the odds of seroconversion decreased dramatically when the baseline antibody level was higher.15 Participants who received influenza vaccines in the previous year had significantly lower odds of seroconversion than those who did not.15 One possible explanation was that repeated vaccination negatively interfered with immunogenicity.16 Surender Khurana et al.17 indicated that repeated vaccination negatively affected antibody binding, antibody affinity maturation, and hemagglutination inhibition responses to H1N1, H3N2, and B strains manufactured by three different vaccine platforms. At the same time, results showed that repeated vaccination failed to induce CD4 T cell activation.7 Studies demonstrated that prior-year vaccination correlated with low production of antibody-secreting cells and reduced effector B-cell responses to new vaccine immunization.18, 19 The concept of antigenic imprinting has been suggested to explain the negative effect of repeated vaccination.20 When contacted with a novel virus strain similar to an individual exposed, the immune response to the original one was predominantly boosted at the expense of response to the subsequent one. These participants' immune systems tended to induce a strong anamnestic response to the original strains, and the production of their memory cells stimulated by the subsequent strains was reduced.
Health conditions were important factors influencing the body's immunity.6 In this study, participants with chronic diseases had a higher risk of lower seroconversion rates. A similar study demonstrated that hypertensive subjects had lower antibody levels against the COVID-19 mRNA vaccine.21 A recent study revealed that this association might result from a dysfunctional immune system.22 A study on antibody responses following vaccination with adjuvanted influenza vaccine in immunocompromised children (including AIDS, congenital immunodeficiency, and autoimmune diseases) showed that their GMT and seroprotection rates were lower compared with immunocompetent children.23 This phenomenon could be due to the defects in their immune system, causing worse responses to the influenza vaccine.24 However, diabetes status seemed to have less impact on the immunogenicity of the influenza vaccine. Sarah Spencer et al.25 found that the serologic response to the influenza vaccine was similar in participants with and without type 2 diabetes mellitus. Daniela Frasca et al.26 found that type 2 diabetes patients had normal in vivo and in vitro B cell responses to the influenza vaccine. The possible reasons for this were that the increase in their serum LPS and sCD14 would stimulate B cells, and the TLR4 expression level in their B cells also increased.26 Therefore, the chronic underlying medical conditions affecting the immune response to the influenza vaccine were complex. These implied that vaccine boosters or different vaccine schedules should be used for patients with chronic diseases to increase vaccination effectiveness.
Participants of different ages also differed in immune responses to the influenza vaccine. In the current study, participants aged 18 to 65 had higher fold changes and seroconversion rates, and this was consistent with previous studies. A Polish study evaluating the influenza virus circulation in the 2015/2016 epidemic season reported that both GMT levels and seroprotection rates of participants aged 0 to 4 years and older than 65 years were lower,27 suggesting the susceptibility of these two age groups to influenza virus. The immune system of infants is not completely developed, and the magnitude and activity of their antigen-presenting cells (APCs), immune cells, and cytokines are lower than in older children and adults.28 For older people, Goodwin et al.29 conducted a quantitative review of studies concerning antibody levels for the influenza vaccine. They reported that the elderly over 65 had significantly lower antibody levels than younger adults, as well as the seroconversion rate, seroprotection rate, and the GMT level. However, the underlying reason for the worse responsiveness to vaccines in the elderly was "immunosenescence", referred to as age-related changes in the immune system.30 Aging negatively affects the body's immune cell repertoire and results in cell-intrinsic defects in lymphocytes.30 These contribute to the deterioration of innate and adaptive immune responses.31 Influenza vaccines can provide moderate protection against viruses, but such protection is reduced in younger children and the elderly, and these two groups of people become vulnerable. Optimized vaccination strategy and new vaccines with improved immunogenicity were needed to reduce influenza-related morbidity and mortality.
Intriguingly, there seemed to be a trend for A/H3N2 that the higher the frequency of common colds, the better the responsiveness. This was observed in both multivariable logistic regression analysis and the rank-sum test. We speculated that the common cold could generate cross-reactive binding antibodies against the influenza vaccine strain,32 similar to Sealy's study33 et al. The study indicated that the pre-existing immunity conferred by an individual's past exposures to common cold human coronaviruses might influence the body’s control for SARS-CoV-2.33 The common cold is caused by well-adapted pathogens and is less harmful to their hosts.34 Therefore, people who often catch a cold have relatively low immunity and are also vulnerable to the influenza virus. Influenza vaccination is necessary for this group of people, who can benefit more from it. However, more research is needed to explore the association between the common cold and the immune response to the influenza vaccines from various aspects, providing more implications for vaccination.
Gender is an important factor affecting the immunogenicity of influenza vaccines.35 Engler et al. found that women had significantly higher geometric mean titer (GMT) than men in the case of different doses and strains.36 However, in the current study, only the antibody fold change for B/Victoria showed a significant difference between the male and female participants. In fact, the effect of gender on vaccine immunity is complex. Besides genetic factors, the difference can also be explained through the divergent levels of sex steroid hormones, which are changing with aging. 35 37 Women seem to lose their immunological advantage after menopause. 35 Therefore, the composition and dosage of influenza vaccines need to be adjusted according to the sex-mediated immunity differences. Future studies need to explore more factors that mediate sex differences in the immune responses deeply and extensively.
This study identified several factors relating to responsiveness to the influenza vaccine and suggested the need for more optimized vaccination strategies for susceptible groups to improve the efficacy of influenza vaccines, which is of great importance for public health. The findings in this study were a supplement to previous studies and may give some new insights into the immunogenicity response to the vaccine. However, there were some limitations in the current study. This study was descriptive, with some participants' characteristics not collected comprehensively, and we did not perform mechanism studies based on the study cohort. The association between the immune response to different strains and host factors should be certain in the future. It is also necessary to perform larger cohort studies and experiments to explore the underlying mechanisms.
The updated position paper on the use of seasonal influenza vaccines published by WHO recommended that older adults, children, health workers, pregnant women, and individuals with comorbidities and underlying conditions be prioritized as target groups.38 In the future, it is of significance to increase vaccination rates for these vulnerable populations and optimize vaccine components and vaccination strategies to improve vaccine efficacy and reduce the morbidity, mortality, and disease burden associated with influenza.