Vaccines have been heralded as the only way out from the ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This conclusion was reached because of the high risk of mortality in the elderly associated with natural infection, which precludes this route to population immunity.
A new preprint, released on the medRxiv* server, describes the kinetics of the antibody response to the earliest approved vaccines against COVID-19, which were developed on a messenger ribonucleic acid (mRNA) platform.
The mRNA vaccines
The mRNA is a molecule that transcribes information on protein synthesis from the genes on the strand of RNA that contains all the genetic information of the virus.
The mRNA used in these vaccines encodes information on the spike protein, which is the protein responsible for viral binding to and entry into the host target cell. The vaccine thus induces the formation of the viral spike antigen within the host, and thus triggers both humoral and cellular immune responses.
Humoral responses occur in the form of multiple antibody subsets, of which both immunoglobulin (Ig) G and IgA are key to neutralization of the virus, but have different parts to play in the immune response, occurring at different stages of infection and at different sites in the host organism.
IgA is the most plentiful Ig in the human body, at 66 mg/kg/day, and is by far the most abundant isotype within the mucosae. Conversely, IgG is most abundant in the blood and within most tissues.
The distribution of IgA being at the mucosal surface of various organs, it is the first to encounter the infectious viral particles, and thus to prevent transmission. Many studies have shown that IgA is more effective than IgG in preventing influenza and SARS-CoV-2.
In fact, an earlier study shows that early neutralizing immune responses to the virus are chiefly due to IgA, which is seven-fold as effective as IgG when the serum concentrations of both are compared for viral neutralization.
This seven-fold increase is also obvious with respect to the temporal changes in the number of IgA-positive plasmablasts displaying homing receptors for the mucosa, and on comparing the amount of neutralizing IgA in airway fluid and in saliva.
The current study aimed to evaluate the titers of IgA and IgG in serum against the SARS-CoV-2 spike antigen in the earliest vaccine recipients. These four individuals were healthcare workers and thus at high priority for the vaccine.
The antibody levels in these workers were measured for a maximum of 80 days from the first dose of the vaccine. The baseline tests for SARS-CoV-2 nucleocapsid (N) and spike (S) antigens were negative.
What were the results?
After the first dose, the serum levels of the spike-directed IgG showed an exponential increase, before eventually evening out at 18-21 days. A similar rise occurred after the second dose, to reach the peak at seven days from the vaccination. Over the rest of the follow-up period, approximately 20-50 days, the IgG values plateaued at about 80% of peak values.
Spike-specific IgA levels showed a similar trend, peaking within the same period as IgG after both first and second doses of the vaccine. However, the drop in titer with IgA subsequent to the maximum titer was significantly more rapid than that with IgG.
IgA antibody levels thus dropped to about half the titer at the peak response, following the first dose. After the booster dose, it peaked and then plateaued at about 40% of the maximal dose, within 50 days of the second injection.
Comparison with earlier research
This pattern of IgG/IgA induction followed by decay in response to the SARS-CoV-2 vaccine agrees with the serum half-life of the various immunoglobulin isotypes, which is 21-28 days vs. 5-6 days for IgA and IgG, respectively.
The fast decrease in serum IgA levels is also in agreement with that reported from a study of the antibody response in natural SARS-CoV-2 infection, in Spanish healthcare workers, with a follow-up period of 3 months.
Another study showed that despite the rapid drop in serum IgA against the spike antigen following natural infection, mucosal IgA concentrations persist longer and may include dimeric IgA molecules with higher neutralizing capacity, at up to 15-fold higher potency compared to the IgA monomer.
In this study, IgAs induced by vaccination and directed against specific antigens were not individually evaluated at mucosal surfaces. Serum IgA may be the source of the mucosal form, arriving at the mucosal site by transduction or being secreted by circulating IgA-secreting plasmablasts possessing a surface molecular profile that directs them towards mucosal surfaces.
Another possibility is that tissue-resident B lymphocytes may undergo isotype class switching within the mucosa to secrete IgA.
What are the implications?
The current study shows the need for further research to arrive at a conclusion about the induction of IgA following mRNA vaccine administration, and its distribution at mucosal sites.
The fact that serum IgG directed against the spike antigen appears to persist following vaccination may indicate that long-term immunity results from two doses of an mRNA vaccine. It may also suggest the utility of this measurement as a biomarker of vaccine responsiveness.
Secondly, the findings show that these vaccines induce spike-specific IgA, thus helping to prevent virus transmission and not just symptomatic disease or infection.
It is noteworthy that the serum IgA levels against the spike antigen drop faster than the corresponding IgG antibody levels. However, the “recall” response, following the booster dose, is much more rapid for both IgG and IgA than the primary response.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.