A US study evaluated the neutralizing antibody response following an infection by the Delta or Omicron variant in individuals having received two doses of vaccine, with or without a booster. These results have been published online in the journal Cell on March 18, 2022.
It is recalled that an infection occurring in a vaccinated individual (post-vaccination infection) is designated by the term breakthrough infection in English. The results suggest that the breakthrough infections due to Omicron are less immunogenic than those due to Delta and may not protect against reinfection or a future more pathogenic variant.
This involved the researchers at the University of California San Francisco evaluating, in doubly vaccinated subjects, some of whom had received a booster dose, the capacity of the antibodies produced after infection with the Delta or Omicron variant to neutralize the strain ancestral Washington (WA-1, whose protein spike is identical to that of the Wuhan strain).
Two types of neutralization tests were carried out. While some have evaluated the ability of antibodies to neutralize live SARS-CoV-2 viruses, others have measured the neutralizing power of antibodies against virus-like particles (VLPs, for virus-like particles). These VLPs mimic a viable virus: they have a morphology similar to infectious SARS-CoV-2 but lack a genome. They are therefore non-infectious because they are unable to replicate. They contain structural viral proteins of SARS-CoV-2, in particular the protein spike (S), the nucleocapsid protein (N), the matrix protein (M), a region of the coat protein (E). These VLPs incorporate all Omicron-specific mutations, not just those present in the protein spike, as is usually the case in most pseudoviruses. These neutralization tests were therefore used against authentic viruses or against particles mimicking a virus carrying specific Omicron mutations.
The researchers first conducted their neutralization tests with plasma samples from 68 individuals enrolled in a prospective cohort. Among them, 15 had received a booster dose and none had been previously infected with SARS-CoV-2.
In vaccinated individuals who had not received a booster dose, neutralizing antibody titers against the Delta variant (assessed by a test using VLPs) were 2.7 times lower than those observed against the ancestral strain . In vaccinated subjects who had not received a booster, the titers of neutralizing antibodies against the Omicron variant (evaluated by a test using VLPs) were 15.4 times lower than those observed against the ancestral strain.
In comparison with the subjects who had not had a booster, those who had received a third dose presented titers 18 times higher in neutralizing antibodies against the ancestral strain. In individuals who received a booster, the titers of neutralizing antibodies against the Delta variant (evaluated by a test using VLPs) were 3.3 times lower than those observed against the ancestral strain. In these same subjects, the titers of neutralizing antibodies against the Omicron variant (evaluated by a test using the VLPs) were 7.4 times lower than those observed against the ancestral strain.
Unsurprisingly, in vaccinated subjects, the researchers also observed that the titers of neutralizing antibodies directed against the Delta and Omicron variants decline over time.
This study indicates that the clinical intensity of the breakthrough infection is associated with higher neutralizing antibody titers. These are generally higher (5 times higher) in the event of moderate to severe Covid-19 disease than when the post-vaccination infection is asymptomatic or leads to a mild clinical form.
The researchers also assessed neutralizing antibody responses and the degree of cross-neutralizing immunity by analyzing plasma samples from 60 vaccinated patients who developed SARS-CoV-2 infection, documented by whole genome sequencing.
Of these 60 cases of breakthrough infection, 28 were due to the Delta variant, 20 to the Omicron variant (lineage BA.1). In 12 other cases, the lineage in question could not be determined due to insufficient respiratory sampling or sequencing not covering the entire viral genome. It is however probable that 11 of these 12 cases corresponded to a post-vaccination infection with the Delta variant insofar as the respiratory samples were taken at a time when 97% of cases were attributable to the Delta variant. A twelfth sample, on the other hand, contained the Omicron variant because it had been carried out in mid-January 2022, when it largely dominated all the others, then responsible for 97% of the cases. Of these 60 cases of infection occurring in vaccinated subjects, 34 corresponded to moderate to severe Covid-19 disease, 13 had received a booster dose and 14 were immunocompromised.
By using neutralization tests with VLP, the researchers observed in the 39 (28+11) patients who had developed a post-vaccination infection by the Delta variant (5 of whom had had a booster) that the titers of neutralizing antibodies against -vis of the ancestral strain were 57 times lower in individuals who had not received a booster dose. They were 3.1 times lower in those who had received a booster.
Concerning the 21 (20+1) patients who developed a post-vaccination infection by the Omicron variant, the researchers analyzed the plasma in 14 cases (including 4 patients who had a booster).
Unlike patients infected with the Delta variant, those with breakthrough infection by Omicron had markedly lower neutralizing antibody titers compared to the ancestral strain. The titers were in fact 5.8 times lower in individuals who had not received a booster dose and about a third of those observed after a booster dose (3.1 times lower). To put it simply, it appears that an infection with Omicron is therefore not equivalent to a third dose of vaccine.
In vaccinated subjects who have developed breakthrough infection by Omicron, the neutralizing antibody response to the Delta variant was weak and vice versa. More specifically, the antibody titers against the Delta variant in the breakthrough infections due to the Omicron variant were respectively 3.3 and 2.2 times lower than those against the ancestral strain, depending on whether the neutralization test used the VLPs or the live virus. In fact, this antibody response was comparable to that observed in uninfected vaccinated subjects. All in all, in the event of infection by Delta or Omicron after vaccination, cross-neutralizing immunity appears to be limited.
Ten times less neutralizing antibodies in post-vaccination infection with Omicron than with Delta
Other experiments have shown that in immunocompetent subjects, vaccinated but not having received a booster, a post-vaccination infection by the Delta variant is accompanied by a titer of neutralizing antibodies against the ancestral strain 10.8 times higher. that in case of breakthrough infection by Omicron. The breakthrough infections due to the Omicron variant are therefore less immunogenic than those due to Delta. They generate lower levels of neutralizing antibodies than infections due to the Delta variant.
This weaker antibody response during a breakthrough infection by Omicron is probably due to the higher proportion of symptomatic or moderate post-vaccination infections (55% with Omicron versus 28.6% with Delta). These are also accompanied by neutralizing antibody titers 12.3 times lower against the ancestral strain compared to what is observed in moderate to severe clinical forms of Covid-19.
A large number of individuals, unvaccinated and vaccinated, have been infected with Omicron, a variant endowed with immune escape and which has largely replaced the Delta variant, which is more pathogenic. This has often been interpreted, even trumpeted, to mean that the emergence of the Omicron variant portends the end of the pandemic, that SARS-CoV-2 will become endemic, and that large sections of the population will definitely acquire immunity against SARS-CoV-2 through natural infection and/or vaccination.
According to the results of this study, this would therefore not be the case insofar as, in a vaccinated person, an infection with Omicron confers much lower protection than that induced by an infection with Delta. According to the authors, “the immunity acquired following a breakthrough infection by Omicron may be of shorter duration than that of a breakthrough infection by other variants, such as Delta, to prevent infection by another more pathogenic variant, should it emerge in the future “. In other words, compared to a post-vaccination infection with Delta, having been infected with Omicron would result in less protection against the risk of reinfection or infection with a future more dangerous variant.
“However, it is reassuring to find that infections occurring in vaccinated individuals are associated with a shorter overall duration of infection and a lower risk of hospitalization and death than in unvaccinated individuals,” temper Charles Chiu, Melanie Ott, Jennifer Doudna, Carl Hanson and their colleagues. And to conclude by recalling that the available data show that the administration of a booster dose leads to robust neutralizing immunity against the Omicron variant.
Mark Gozlan (Follow me on TwitterFacebook, LinkedIn, and on my new blog ‘Diabetes in all states’, devoted to the thousand and one facets of diabetes. Already three tickets)
To know more :
Servellita V, Syed AM, Morris MK, et al. Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants. Cell. Available online 18 March 2022. doi: 10.1016/j.cell.2022.03.019
Amanatidou E, Gkiouliava A, Pella E, et al. Breakthrough infections after COVID-19 vaccination: Insights, perspectives and challenges. Metabol Open. 2022 Mar 17;14:100180. doi: 10.1016/j.metop.2022.100180
Wratil PR, Stern M, Priller A, et al. Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern. NatMed. 2022 Mar;28(3):496-503. doi: 10.1038/s41591-022-01715-4