In a recent study published in iScience, researchers assessed the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with a non-Omicron variant on SARS-CoV-2 BA.4/5 neutralization.

Study: Non-Omicron breakthrough infection with higher viral load and longer vaccination-infection interval improves SARS-CoV-2 BA.4/5 neutralization. Image Credit: ktsdesign/Shutterstock

Background

The interval between vaccination and infection influences the production of cross-neutralizing antibodies against the SARS-CoV-2 Omicron BA.1 variant; an extended period ends in a better generation of cross-neutralizing antibodies. Moreover, an extended gap between the initial two vaccinations elicits more neutralizing in addition to spike (S)-binding antibodies against Omicron BA.1 and non-Omicron variants of concern (VOCs) than the traditional dose interval.

Other variables, including symptoms, the causal viral strain, and viral replication, are anticipated to influence the immune system’s response to SARS-CoV-2 infection. The first causes of humoral immune responses against SARS-CoV-2 during breakthrough infections haven’t been thoroughly explained.

Concerning the study

In the current study, the team analyzed the associations between the magnitude of cross-neutralization activity elicited against SARS-CoV-2 variants, mainly Omicron sub-lineage viruses.

Using upper respiratory materials obtained inside 4 days of SARS-CoV-2 diagnosis or symptom onset, the team undertook a virological characterization of 220 breakthrough coronavirus disease 2019 (COVID-19) patients diagnosed post-second immunization. The team described the acute phases because the span inside 4 days of diagnosis, while the convalescent phase was seven days following diagnosis or symptom onset.

For added evaluation, 26 cases during which sera were obtained throughout the acute phase in addition to 51 cases during which sera were collected throughout the convalescent phase, were included. In these instances, serum-neutralizing activity was evaluated using live virus-based techniques.

Results

Polymerase chain response (PCR) and evaluation of the viral genome performed for spike mutation detection revealed that the majority infected viruses were either SARS-CoV-2 Alpha or Delta variants. In upper respiratory samples, infectious viral titers and viral ribonucleic acid (RNA) loads were considerably greater in Delta-infected people than in Alpha-infected individuals. Nonetheless,  infectious viral titers and viral RNA loads were positively related to the identical magnitude in each variants, indicating no difference between the variants within the association between the infectious viral quantity and viral RNA levels.

These findings indicate that Delta replicated more rapidly within the upper respiratory tract of individuals with a breakthrough infection. Throughout the convalescent period, the anti-S antibody titers were akin to cases with breakthrough infection with no report of prior infection.

Within the convalescent phase, neutralizing activity related to all variants was greater than within the acute phase. The neutralizing activity of acute phase sera against Beta, Delta, and Omicron BA.1, BA.2, and BA.4/5 viruses were lower than that of the ancestral strain, while over half of all of the BA.4/5 neutralizing titers were found to be lower than the detection limit. The neutralizing activity of convalescent phase sera against the Beta and Omicron BA.1, BA.2, and BA.4/5 viruses was lower than that of the unique strain.

Notably, there have been no discernible variations in neutralizing activity between BA.1, BA.2, and BA.4/5 viruses amongst serum samples obtained from convalescent-phase patients, indicating minor antigenic differences across Omicron sub-lineages detected in non-Omicron breakthrough serum samples.

The convalescent and acute neutralization titers against BA.2 were lower than those against the ancestral strain. Convalescent phase sera obtained from Delta breakthrough sera had more neutralizing activity against Beta and ancestral variants than convalescent phase sera from Alpha breakthrough infections, but each exhibited equal neutralization activity against Delta and Alpha variants.

Infection with the Delta variant was favorably linked with neutralization titers against the ancestral and Beta viruses, supporting the aforementioned results. In contrast, the period between vaccination and infection was positively linked with neutralization titers to ancestral, Beta, and Omicron BA.1, BA.2, and BA.4/5 infections in convalescent-phase sera.

As well as, there was a considerable correlation between viral load within the upper respiratory and neutralization titers in response to all variants in convalescent-phase serum samples. This showed that the viral load detected within the upper respiratory tract during diagnosis modulated antibody responses throughout the convalescent period following a recent infection.

The team investigated the association of the causal viral lineage with variant-serum distances and observed no changes between the convalescent and acute phases. This showed that the extent of serum neutralization didn’t differ between the Delta and Alpha breakthrough infections. Moreover, the Delta and Alpha breakthrough infections affected the magnitude of neutralization against diverse antigenic variants equivalently.

Conclusion

Overall, the study findings discovered that non-Omicron breakthrough infections induced strong cross-neutralizing motion against SARS-CoV-2 Omicron variants similar to the BA.4/5 sub-lineage across the antigenic barrier. The outcomes indicated that the duration of the post-vaccination incubation interval, and never the antigenicity related to the infecting virus or the viral load detected within the upper respiratory tract, is a vital consider extending neutralization to antigenically different viral variants.