Breakthrough Omicron infections reduces protection against reinfection or infection from future variants

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A latest study by researchers from University of California-San Francisco, University of California-Berkeley, California Department of Public Health and Gladstone Institutes-San Francisco has shockingly found that in reality, breakthrough Omicron infections reduces protection against reinfection or infection from future variants.

The study findings have been peer reviewed and published in the in the prestigious journal: Cell. https://www.cell.com/cell/fulltext/S0092-8674(22)00329-4

Here we used VLP and live virus neutralization assays to investigate neutralizing antibody responses in 128 vaccinated individuals, both boosted and unboosted, and after Delta and Omicron vaccine breakthrough infections.

Our results suggest that vaccine boosting and/or breakthrough infections confer broad hybrid immunity by increasing neutralizing antibody titers against WT to levels comparable to those achieved shortly after completion of a primary vaccine series and prior to waning, with higher relative immunity against the infecting variant.

Notably, Delta-specific titers in Delta breakthrough infections rose to become comparable to levels against WT, while Omicron-specific titers in Omicron breakthrough infections rose to become comparable to levels against Delta. We also found that the magnitude of increase in neutralization titers against WT is greater with Delta than with Omicron breakthrough infections (10.8-fold, p=0.037) and for infections that are more clinically severe (12.3-fold, p=0.020).

Our results are consistent with those from studies by Wratil, et al (2022) and Walls, et al. (2022) that examined neutralizing responses in Delta and Omicron breakthrough infections (n=31) and Delta breakthrough infections (n=15), respectively, and found robust increases in antibody titers to WT and cross-neutralization of other variants. Interestingly, the study by Wratil, et al. (2022) also found that sera from Delta breakthrough infections cross-neutralized Omicron less well.

Another study by Khan, et al. (2021) investigated the role that cross-neutralizing immunity plays in Omicron breakthrough infections. The investigators reported that sera from patients with Omicron breakthrough infections enhanced Delta virus neutralization to a limited extent (4.4-fold), but that immunity elicited against the specific infecting variant (Omicron) was higher (17.4-fold).

A few other published studies have looked at the effect of boosting on neutralization of Omicron. Pseudovirus studies from Laurie, et al. (2022) and Liu, et al. (2022) reported 4 to 8-fold and mean 6-fold reductions in neutralization titers, respectively, against Omicron in boosted individuals.

These reductions are comparable to the 7.4-fold reduction that we observed using the VLP assay. However, these modest reductions are likely offset by the substantial increase in neutralizing antibody titers against WT conferred by the booster dose that we observed in the current study, which also has been reported by Gruell, et al. (2022). Taken together, these results indicate that booster immunization provides robust neutralizing immunity against the Omicron variant and highlight the importance of vaccine boosters in enhancing immunity to both existing and novel variants.

Our findings have implications regarding the likelihood that Omicron infections will provide mass immunization on the population level against SARS-CoV-2. Widespread infections from Omicron globally in both vaccinated and unvaccinated persons have been reported, although Omicron has been shown to cause milder disease with reduced risk of hospitalization and death relative to prior lineages (Wolter et al., 2022).

In addition, epidemiologic data to date suggest that Omicron has outcompeted more pathogenic circulating variants such as Delta (Gangavarapu et al., 2020). These observations raise the prospect that Omicron may be a harbinger of the end of the pandemic as SARS-CoV-2 becomes an endemic virus and broad swaths of the population acquire vaccine-mediated and/or natural immunity. However, in the current study, we found that Omicron breakthrough infections generate a slower rise in and lower levels of neutralizing antibodies than Delta.

A muted neutralizing antibody response with Omicron breakthrough infections relative to Delta may be due to an increased proportion of asymptomatic or mild infections in the Omicron cohort (55.0% versus 28.6% for Delta, p=0.083), or decreased replication and virulence along with attenuated disease associated with Omicron infection (Halfmann, et al., 2022; Hui, et al., 2022).

Thus, immunity from Omicron breakthrough infection may be less durable than breakthrough infection from other variants such as Delta in preventing infection from another, more pathogenic variant, should it emerge in the future. However, it is reassuring that breakthrough infections in vaccine recipients are associated with both shorter overall duration of infection (Kissler, et al., 2021) and decreased risk of hospitalization and death (Tenforde, et al., 2022) compared to infection in unvaccinated individuals.

In the current study, live virus neutralization studies showed 2.5-fold lower titers than those using VLPs, which are similar to spike-pseudotyped viruses. Most SARS-CoV-2 neutralization studies reported to date have used pseudoviruses because the protocols for running these assays have been reliable, safe, and convenient. Of note, the VLPs used in this study incorporate all the Omicron-specific mutations found in the structural spike, nucleocapsid, matrix, and fusion proteins (Syed et al. 2022), and not only in the spike protein, as is the case for most pseudovirus assays.

One possibility for the discrepant neutralization results may be the use of different cell lines for the VLP (293T) and live virus (Vero) assays, although both cell lines are highly susceptible and permissive to SARS-CoV-2 given stable expression of TMPRSS2 (transmembrane serine protease 2) and the ACE2 (angiotensin converting enzyme 2) receptor (Hoffmann et al. 2020; Case et al. 2020).

A more likely explanation is that pseudoviruses and VLPs typically only measure the capacity of the virus to enter cells during a single round of infection, whereas live virus assays measure virus infection over several rounds of infection since the reporting endpoints rely on the appearance of cytopathic effect, during which the viruses have already spread from cell-to-cell. Therefore, the reported extent of immune evasion associated with Omicron infection may be underestimated with the use of pseudovirus assays alone.

The utility of the FDA authorized serologic assay results as correlates of immune protection with respect to infection from different variants is still under investigation (Gilbert et al. 2021). Here we found that spike IgG quantitative and neutralizing antibody results are less correlated with Delta and Omicron infections and thus less predictive of neutralizing immunity.

The degree of correlation was inversely related to the extent of neutralizing antibody evasion associated with the variant, which is to be expected since the IgG quantitative assay targets the spike protein from an ancestral WA-1 lineage. Despite the presence of multiple spike mutations, measured antibody levels of 103–104 for Delta and >105 for Omicron still reliably predicted neutralization. Nevertheless, serologic assays tailored to individual variants or assays directly measuring neutralization will likely be needed for more accurate assessments of neutralizing immunity.

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