Since the onset of the Coronavirus Disease 2019 (COVID-19) pandemic, it has brought about episodic waves of increased infections due to the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. These variants have higher transmissibility and resistance to immune responses that are elicited by the current vaccines.
The World Health Organization has classified the most epidemiologically important variants as variants of concern (VOC) which include Alpha, Beta, Delta, and Omicron.
Currently, the Omicron variant (including sub-lineages BA.1 and BA.2) is the predominant circulating variant throughout the world. The spike protein of the Omicron variant is reported to have 39 amino acid changes out of which approximately half fall within the receptor-binding domain (RBD) which binds to the human receptor angiotensin-converting enzyme 2 (ACE2). Since all known neutralizing antibodies mostly target the RBD, mutations within this region lead to severe loss in neutralizing activity of approved monoclonal antibody therapeutics.
Since antigenic exposure from boosters and breakthrough infections can boost serological immunity, third-dose vaccine booster campaigns are underway to control the ongoing Omicron wave. Although vaccine breakthrough infections can directly train the immune system against variant spike proteins, they are associated with medical risks. Booster vaccinations on the other hand are generally safe and effectively increase the neutralizing response against Omicron. However, the durability of responses due to boosting and breakthrough infection and whether they provide greater protection from reinfection with Omicron or future variants is unknown.
A new study posted to the pre-print server medRxiv* examined the serological immune responses and antibody-dependent cell-mediated phagocytosis in those individuals who had either received two doses of a standard vaccine regime, or a booster dose following the regime, or a breakthrough infection following vaccination.
About the study
The study involved two- and three-dose group participants as well as breakthrough participants. The two- and three-dose group participants had no COVID-19 history. For the breakthrough participants, a polymerase chain reaction (PCR) test was done to confirm SARS-CoV-2 infection. Blood samples were collected from all the participants for further analysis. The vaccine used in this stud was BNT162b2 (Pfizer) and only individuals with no immunocompromising conditions were included.
Thereafter, an enzyme-linked immunosorbent assay (ELISA) was performed followed by antibody-dependent cellular phagocytosis (ADCP). SARS-CoV-2 was then propagated in cell cultures and viral stock titers were calculated in focus forming units (FFU) that were based on dilution factor and volume used for infection. Finally, focus reduction neutralization test (FRNT) assays were performed.
Study findings
The results indicated that the half-maximal antibody binding in ELISA (EC50) to full-length SARS-CoV-2 spike was 223 percent higher in the three-dose group and 278 percent higher in the breakthrough group as compared to the two-dose group. The spike RBD-specific antibodies were found to increase in the three-dose group but not in the breakthrough group. The increase in spike RBD-specific antibodies was reported to be 259 percent higher in the three-dose group as compared to the two-dose group.
Additionally, the spike-specific IgG levels were found to be 224 percent and 261 percent higher and spike-specific IgA levels were found to be 221 percent and 279 percent higher in the three-dose and breakthrough groups respectively as compared to the two-dose group. However, the IgM levels did not differ significantly among the groups.
ADCP was also found to increase in the three-dose and breakthrough group as compared to the two-dose group. The geometric mean titers (GMT) that showed 50 percent neutralization of the original SARS-CoV-2 virus (WA1, Wuhan strain) were reported to be 463 percent and 732 percent higher for the three-dose and breakthrough groups as compared to the two-dose group. For Delta strain, the GMT was found to be 948 percent and 424 percent higher for the breakthrough and three-dose group as compared to the two-dose group. For the Omicron strain, the GMT was found to be 1156 percent and 1810 percent higher for the three-dose and breakthrough group as compared to the two-dose group.
Furthermore, the neutralizing titer was found to correlate strongly with the neutralization of WA1 and Delta strain. However, for the Omicron strain, the correlation was found to be weaker for the two-dose group. The neutralizing potency index (NPI) which is the ratio of live-virus neutralization to spike-specific antibody EC50 for WA1 was found to be 0.60 for the two-dose group, 1.10 for the three-dose group, and 1.91 for the breakthrough group. For Delta, it was found to be 0.30, 0.52, and 0.93 and for Omicron it was found to be 0.03, 0.15, and 0.20 for two-dose, three-dose, and breakthrough groups, respectively.
The ratio of neutralization for each variant to WA1 neutralization for Delta was found to be 0.42 for two-dose, 0.43 for three-dose, and 0.55 for the breakthrough group. For Omicron it was 0.06 for two-dose, 0.12 for three-dose, and 0.13 for the breakthrough group. Also, a negative correlation was found between age and WA1 neutralizing titer for the two-dose and three-dose groups but not for the breakthrough group.
The current study, therefore, demonstrates that the foundation of immunity can be further increased by boosting or breakthrough infections, even for immune-resistant variants such as Omicron. The increased immunity due to booster vaccinations or breakthrough infections throughout the world can thus lead to the acquirement of potent immune responses that can help to protect against the future SARS-CoV-2 variants.
*Important notice
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.
