Study suggests antibodies triggered by COVID-19 mRNA vaccination may depend on prior infection history

In a recent article published in Scientific Reports, researchers evaluated distinct immune responses to messenger ribonucleic acid (mRNA) and vector-based coronavirus disease 2019 (COVID-19) vaccines, and natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. 

Specifically, they monitored vaccination- or prior infection-induced SARS-CoV-2 spike(S)-specific immunoglobulin G (IgG) isotypes and subclasses in the human serum in a three to four-month period to estimate the stability of the anti-SARS-CoV-2 humoral immune response. 

The team examined the pattern of S-specific IgGs induced by the SARS-CoV-2 infection and different types of COVID-19 vaccines and whether the chronological order of natural virus infection and vaccination influenced it.

Background

Different COVID-19 vaccines are available, ranging from inactivated to non-replicating viral vector and mRNA vaccines. Previous studies have established that SARS-CoV-2 naïve individuals and previously infected individuals show distinct immune responses to vaccination. 
IgG is the most abundant immunoglobulin isotype in human serum. Each subclass of IgG has a unique profile related to antigen binding, immune complex formation, complement activation, and triggering of effector cell activation. 

After antigenic stimuli, especially viral protein antigens, two complement-activating IgG subclasses, IgG3 and IgG1, are secreted first, whereas IgG2 and IgG4, which attenuate inflammation without complement activation, are secreted later.  
Carbohydrate antigens stimulate IgG2, whereas prolonged antigen stimulations result in IgG4 secretion.

There is limited understanding of the relationship between specific IgG titer and memory recall response elicited in response to SARS-CoV-2, although single-cell sequencing and flow cytometry data recently showed IgG4-switched, S-binding memory B cell response to mRNA vaccination. 
In another study, it was suggested that adenovirus-based vaccines do not elicit a long-term S-specific IgG4 response.

About the study

In the present study, researchers created two cohorts: a vaccinated cohort comprising 47 healthy volunteers recruited in Budapest, Hungary, and a COVID-19 cohort constituting 26 convalescent serum participants (CONV) and 101 hospitalized COVID-19 patients (HOSP).

Eleven individuals from the vaccinated cohort received vector-based (Sputnik) vaccines and 36 received mRNA (Moderna) vaccines. All vaccinated individuals were positive for SARS-CoV-2 S-specific IgG antibodies. 

Vaccinated individuals were either: infected before mRNA vaccination (INF → mRNA); infected after mRNA vaccination (mRNA → INF); not infected mRNA vaccination (mRNA/no INF); or not infected vector vaccination (Vector/no INF). 

The team collected serum samples on median day 128 post-booster vaccination and from CONV and HOSP patients on median days 54 and 21, respectively. They also monitored 15 mRNA-vaccinated volunteers on median days 37 and 160 post-booster.

The researchers detected IgG antibodies against SARS-CoV-2 S and nucleocapsid (N) proteins using commercial assays. They used an in-house enzyme-linked immunosorbent assay (ELISA) to determine total S-specific IgG and each S-specific IgG subclass.

They used nephelometric assay to quantify total serum IgG and IgG1–4 subclasses. It helped them determine the percentage of each S-specific IgG subclass relative to the sum of all IgGs in both study cohorts. They also computed the average proportion of individuals for each IgG subclass in the respective group.

Results

The current study had many important findings. First, vector-based vaccine recipients had lower total S-specific IgG levels than mRNA vaccine recipients within four to five months post-booster vaccination. 

Regarding the pattern of IgG subclasses, it was comparable for individuals infected before mRNA vaccinations and those who received vector-based vaccines, and even for COVID-19 patients who received no vaccine. COVID-19 patients predominantly had S-specific IgG1/G3 subclasses in serum on the median of 21 days post-infection. 
However, the pattern of S-specific IgG subclasses varied in mRNA-vaccinated individuals with and without prior (natural) infection. 

Interestingly, the switch to S-specific IgG4/G2 occurred exclusively in mRNA vaccine recipients or mRNA → INF group. These distal IgG subclasses also surged in individuals experiencing a breakthrough infection three months or later post-boosting within 40 days of the breakthrough infection.

Additionally, the INF → mRNA group had lower and constant S-specific IgG2/G4 levels than other mRNA vaccine-receiving groups four months after boosting. This response was lacking in recipients of vector-based COVID-19 vaccines.

Furthermore, increased S-specific IgG1/G2/G4 responses in the mRNA → INF group indicated a memory B cell recall response, which decreased in the mRNA/no INF group. 

In this study, mRNA-based COVID-19 vaccines generated LLPCs with the IgG4 subclass, highlighting how the vaccine composition may be important in the induction of the IgG4 subclass. It also highlighted that priming immunization by mRNA vaccines could be necessary for eliciting high IgG4 subclass distribution in the secondary immune response as it reactivated pre-existing S-specific IgG4 memory B cells.

Conclusions

The current study confirmed findings from previous studies that COVID-19 mRNA vaccines induced a high proportion of S-specific IgG4 responses, while this response was missing among the recipients who received vaccination after natural SARS-CoV-2 infection and infection naïve individuals vaccinated with vector-based vaccines. 

This data could be relevant for future mRNA-based vaccine development. Further studies could validate these observations.