The COVID-19 recombinant subunit vaccines have demonstrated remarkable success in providing protection against infections and diseases. However, there are notable limitations, particularly the existing gap in clinical trials for individuals aged 60 and above with underlying health conditions. In this prospectively planned cohort study, we conducted the first-ever evaluation of the immune response elicited by Zifivax vaccination and its effectiveness in safeguarding against BA.5 or BF.7 variants infection in AD patients in a real-world setting.
Vaccine-induced nAbs play a critical role in protection from SARS-CoV-2 infection. In this study, RBD-IgG WT levels exhibited a steady increase after each vaccination, with a notable spike following infection with BA.5 or BF.7 variants. Antibody levels generated without vaccination post-infection, similar to those after the second vaccination, were considered lower than those with vaccination after infection. This suggested that subunit vaccines trigger a more robust humoral immune response in vivo compared to no vaccination. Vaccination also induced a memory B cell immune response, resulting in the rapid production of substantial amounts of specific protective antibodies post-infection. Following the second dose of immunization, there was a notable rise in RBD-IgG antibody concentrations and antibody response rates, which further increased after the third dose. There was no discernible difference between the antibody response rates after the second and third doses. However, it's essential to highlight that in serum samples with elevated RBD-IgG antibody concentrations, there was a significantly heightened pseudovirus neutralizing activity observed after the third vaccination compared to the second one. This underscores the significance of booster injections in AD patients, particularly those exhibiting robust immune responses. We also observed a strong correlation between RBD-IgG antibody levels and the nAbs activities, which has been confirmed by previous studies[24].
The humoral immune response triggered by COVID-19 subunit vaccines, designed to combat the original strain, was observed to have cross-reactivity against various variants. AD patients who received the third dose exhibited comparable RBD-IgG levels against Delta (L452R,T478K) and Omicron (BA.5), with RBD-IgG levels against Omicron BA.5 slightly lower than those against WT and Delta post Omicron infection. The vaccines demonstrated substantial protection against various variants, although a slight reduction in effectiveness may occur, especially following infection with BA.5 or BF.7 variants. In the AD-UV cohort, the BD-IgG levels against WT, Delta, and BA.5 variants were significantly lower compared to those in the AD-V cohort.
On the cellular immunity front, unvaccinated AD patients showed a significant elevation in both Th1 and Th2 type cytokines after infection with Omicron BA.5 or BF.7. These levels were higher compared to those observed after infection in the AD-V cohort, suggesting that a lack of vaccination may easily lead to a cytokine storm following infection. Cytokine storm-like syndrome can result in various abnormalities and tissue damage and even death[31]. Cytokine storms in COVID-19 patients are associated with interleukin-6 (IL-6), which appears to be an indicator of disease severity[32]. Studies have indicated that a decline in IL-6 levels and IFN-λ levels exceeding 35 pg/mL may signal clinical severity and impending death[33]. In our study, unvaccinated deceased donors had higher levels of IL-6 and IL-10 after infection with SARS-CoV-2, which also coincided. In the monitoring of cytokine dynamics after vaccine immunization, IL-2 and IL-13 were found to have opposite trends; however, both increased after infection. After the first and third doses of vaccination, inflammation is promoted, and anti-inflammatory after the second dose plays a key role, which may indicate that the strengthening of the adaptive immune response has a complementary effect, and the anti-inflammatory and pro-inflammatory cytokines maintain a homeostasis in the body after infection and participate in the antiviral response. This suggests that a higher Th-1/Th-2 immune response can be followed by booster immunity, providing a more robust way to eliminate the virus via mediation of cell-mediated cytotoxic effects and opsonistic phagocytosis by macrophages[34, 35].
The AD vaccination population included in this study was composed of middle-aged and elderly individuals (51 to 99, median 84), divided into 51–79, 80–89, and 90–99 according to age. There was no statistically significant difference in the concentration of neutralizing antibodies after each dose of immunization, and the concentration of RBD-IgG Ab in volunteers over 90 years of age after natural infection was slightly lower than that of volunteers under 80 years of age (p = 0.044). In the phase 1 trial[9], the seroconversion rate of RBD-IgG Ab after the second and third doses was 100% in young adults aged 18–59, and the seroprevalence rates in our study were 73.20% and 81.11%, respectively, suggesting that old age or Alzheimer's disease may have an impact on the body's humoral immune response.
Women frequently exhibit more robust immune responses to vaccines and infection[36, 37]. This heightened response is likely influenced by hormonal factors and the presence of two X chromosomes in women, providing a broader array of immune-related genes[38, 39]. The expression of ACE2 is regulated by estrogen, a significant hormone-related difference between men and women. Estrogen is also a regulator of gene expression and function of various innate immune cells (macrophages, core solo cells, dendritic cells, etc.), and its receptors are present on the surface of various immune cells[36, 37]. In this study, it is important to note that without immune protection from the vaccine, women with SARS-CoV-2 infection produced higher concentrations of RBD-IgG Ab than men (p = 0.027).
In addition, we found that the level of immune response was generally low in AD with cardiopulmonary disease. This finding may be related to the fact that endothelial cells, cardiac stromal cells, and cardiomyocytes in the heart interact with immune cells to regulate the body's metabolism to adapt to the development of infection and inflammation[40].
Cough, sputum and fever are the most common symptoms in patients with Covid-19, and we found that donors who died after SARS-CoV-2 infection, regardless of whether they were vaccinated or not, produced less RBD-IgG than survivors. This suggests that immunocompromised individauls are more likely to face severe consequences when fighting viral infections. Furthermore, vaccination corresponds with a higher survival rate and survival time than no vaccination, which further validates the effectiveness of subunit vaccines.