Worrisome findings were discovered in a new study by researchers from the Finnish Institute for Health and Welfare, Helsinki, Finland in which it was found that among the elderly, the antibody concentrations measured a month after a booster dose was low. Furthermore, not all of the elderly study participants had NAbs against the Beta and Omicron variants.
The study findings were published on a preprint server and are currently being peer reviewed.
Following a booster vaccination, given at 6 to 9 months following the second COVID-19 mRNA vaccine dose, we found high anti-S IgG and detectable NAb concentrations suggesting cross-protection against all variants among HCWs. The anti-S IgG concentrations and the ability to neutralize variants including Omicron remained equally high in samples collected from HCW from 1 to up to 2.5 months following the booster.
However, among the frail elderly living in residential care home the antibody concentrations measured a month after the booster dose were lower compared to those among HCW and not all subjects had NAbs against the Beta and Omicron variants.
The age-dependency of the antibody responses suggests that protection against breakthrough infections following a booster dose may be partial and transient in the frail elderly. Antibody responses to COVID-19 vaccination have been shown to correlate negatively with age; vaccination induces highest antibody responses in younger subjects, and lower among subjects aged 65 and older (11, 22, 23). The concentration of NAbs has also been shown to decline faster with increasing age (24, 25).
Furthermore, the response to a booster vaccination is likely dose dependent. The mRNA content in the Comirnaty vaccine is 30 µg compared to 100 µg in the Spikevax; the currently licensed booster dose for Spikevax is 50 µg. A 50 µg Spikevax booster dose was shown to markedly increase the NAb titers against Omicron in subjects previously immunized with two doses of the Spikevax vaccine (26).
Preliminary data indicates that a full dose would result in two-fold concentration of neutralizing antibodies against the Omicron variant (27). In this study we found that the HCWs who received a full dose of Spikevax as a booster tended to have higher concentrations of cross-neutralizing antibodies compared to those vaccinated with Comirnaty (2.4-fold against Omicron). However, the difference was not statistically significant due to the small number of subjects.
Effectiveness against infection and severe disease has been reported to be higher for Spikevax compared to Comirnaty (28). In subjects vaccinated with two doses of a mRNA vaccine, Spikevax has been shown to induce two-fold antibody concentrations compared to Comirnaty (23).
A high concentration of neutralizing antibodies has previously been shown to correlate with protection against breakthrough infections (29, 30). These data suggest that the stronger the initial immune response to the vaccine, the longer the immunity will persist. Also, our finding that the booster vaccination induced weaker immune responses among the elderly subjects suggests that the added benefit of a booster vaccination against breakthrough infections is likely shorter with older age.
The ability of sera from subjects vaccinated with two doses of a mRNA vaccine (Comirnaty), collected 56 days following the first vaccine dose, to neutralize Omicron variants has been shown to be markedly reduced compared to the ancestral, vaccine-type virus (20).
Similar findings of very low NAb activity against Omicron were reported in the South-African study of subjects vaccinated with two doses of Comirnaty vaccine (19). Another study using live virus neutralization assay found that subjects recently vaccinated with two doses of an adenovirus vector vaccine (Vaxzevria) or mRNA vaccine (Comirnaty) with an extended interval of 8 to 11 weeks between the two vaccine doses had substantially reduced NAb titers against Omicron, but only some subjects not having any Nab (2).
A longer interval between the two doses of the primary series has been shown to result in significantly higher antibody responses indicative of at least partial booster response (31, 32). A booster vaccination, when given as a third dose several months after the second dose, has been shown to significantly increase the IgG and NAb concentrations (32, 33) and markedly improve neutralization of the Omicron variant (26). This is in line with our finding of positive NAb titers against Omicron in all working age subjects, who had received the booster vaccination.
We also found that the anti-S IgG concentrations among previously infected, once-vaccinated subjects were high and NAb titers variable, but comparable to the antibody concentrations following a third vaccine dose among the HCWs. The South-African study also reported that all the previously infected and subsequently vaccinated subjects (5/5) had neutralizing antibodies against Omicron (19).
The kinetics of antibody concentrations following infection may be different compared to vaccine-induced immunity, and the breadth of cross-protective immunity may be qualitatively different. Data suggests that although vaccination may induce higher initial antibody concentrations compared to infection, these antibodies appear to decline much faster (34).
A follow-up study of 2653 subjects vaccinated with two doses of Comirnaty, and 4361 convalescent COVID-19 patients found that IgG antibody titers decreased by up to 40% each subsequent month in vaccinated subjects, while in the convalescents they decreased by less than 5% per month (34).
We have previously shown that anti-S IgG antibodies can be detected up to 13 months following SARS-CoV-2 infection in 97% of the subjects, and that cross-protective NAb against Alpha, Beta and Delta variants persisted in the majority subjects with severe COVID-19 disease (35).
NAb levels induced by infection or vaccination are predictive of protection from symptomatic SARS-CoV-2 infection (17, 29, 30). Although no exact serological correlates have been established, protection from infection likely requires higher NAb levels, whereas the estimated NAb level for protection from severe infection is sixfold lower (Khoury).
SARS-CoV-2 infection induces long-lived bone marrow plasma cells that continue to produce antibodies which likely explains why following a rapid decline of antibody concentrations during the first few months, low but stable concentrations can be detected a year after infection (36).
Circulating, resting memory B cells have also been detected in convalescent individuals (36); a memory B-cell response to SARS-CoV-2 evolves during the first 6 months after infection, characterized with greater somatic hypermutation, resistance to mutations in the receptor binding domain of the spike protein, and increased potency (37).
It is likely that persistent antigen stimulation in previously infected subjects drives this type of maturation of the B cell response. In vaccinated subjects, a booster dose is expected to induce a memory B cell response. In previously infected subjects, vaccination with a single dose of a mRNA vaccine induced not only higher NAb concentrations compared to naïve subjects, but also higher affinity of antibodies, suggesting that in convalescent individuals, the first vaccination recalls pre-existing memory B cells against SARS-CoV-2 that undergo rapid affinity maturation (38).
Higher antibody affinity was found to correlate with improved NAb titers against multiple SARS-CoV-2 variants (38). Susceptibility to infection increases over time, as the level of NAbs declines, especially against antigenically different strains such as Omicron (16). However, boosting of immunity with 3rd doses not only increases the concentration of antibodies, but also improves the quality of the B cell response, and potential long-term immunity against severe COVID-19 disease.
We acknowledge several limitations in our study due to the small number of subjects and HCW gender distribution. Also, in HCW and elderly subjects, we analyzed sera after the 3rd dose, but we did not have pre-booster samples available for comparison. However, pre-booster samples likely had very low NAb titers as low Nab activity against Omicron has been reported following the second dose (19, 20, 26); and especially as 6 to 9 months had passed before the 3rd dose was administered. In this study we only assessed humoral immune responses that are critical immune mechanisms reducing infection.
SARS-CoV-2 infection and vaccination also induce durable T-cell immunity, which targets multiple epitopes in the SARS-CoV-2 spike protein and is likely to enhance protection against severe COVID-19 disease against SARS-CoV-2 variants (39).
Analysis of the mutations in the spike protein sequence of the Omicron variant with computational modelling suggested that the T cell response against Omicron would remain broadly cross-protective, as only a small number of the CD4+ and CD8+ T cell epitopes, and none of the immunodominant epitopes, are affected by the Omicron specific mutations (40).
In summary, the results of our study support previous findings indicating that COVID-19 booster vaccinations raise IgG concentrations, although NAb titers remain low against Omicron compared to WT and Delta variants. In this study we were able to demonstrate measurable NAbs against Delta, Beta and Omicron VOCs up to 2.5 months after 3rd mRNA vaccine dose in adults, whereas some elderly subjects did not have neutralization capacity against Beta and Omicron variants at 1 month after 3rd dose.
We observed that the NAb titers against Omicron were barely detectable already 1 month post mild SARS-CoV-2 infection caused by WT virus, Alpha or Beta variant, suggesting an increased risk of reinfection caused by Omicron. However, single mRNA COVID-19 vaccine dose after SARS-CoV-2 infection induced NAb titers comparable to 3rd mRNA COVID-19 vaccination.
Booster vaccinations likely improve protection against infections at least temporarily, which may help reduce transmission of the virus in the pandemic situation. Immunity against severe disease is also based on memory B cells and T-cell-mediated immunity, which is expected to improve and last longer after booster vaccination.