Neutralization of SARS-CoV-2 Deltacron and BA.3 variants |  NEJM

Neutralization of SARS-CoV-2 Deltacron and BA.3 variants | NEJM

To the editor:

During the coronavirus 2019 (Covid-19) pandemic, the BA.1, BA.2, and BA.3 sub-strains of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-) emerged. 2) Serious concern about the sustainability of vaccine-induced immunity and infection in the face of the continuing evolution of the virus. This worrying viral evolution was exacerbated by the recombination of the omicron variant with the B.1.617.2 (delta) variant.1-3 The ability of deltacrine variants to evade immunity induced by vaccination or previous infection remains unclear.

Here, we used a pseudotyped virus neutralization assay4 To examine neutralizing antibody titers in serum samples obtained from vaccinated healthcare workers at The Ohio State University Wexner Medical Center as well as from patients who tested positive for COVID-19 during delta and omicron waves in the Columbus, Ohio area. We evaluated neutralizing antibody titers against the progenitor SARS-CoV-2 strain carrying the D614G mutation, along with BA.3 and deltacron variants not previously studied, and compared the responses with previously reported results for BA.1 and BA. 2 and delta variables (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).5

Neutralize the BA.3 Omicron and Deltacron variants.

Shown is the neutralization of antibody titer against virus pseudotype with spike protein of SARS-CoV-2 (SARS-CoV-2) carrying the D614G mutation, along with BA.3 and deltacron variants, in 10 serum samples obtained from healthcare Workers who received two doses of mRNA vaccine (panel A) and of the same workers who received three doses of mRNA vaccine (panel B). Neutralizing antibody titers are also shown in samples obtained from 18 patients admitted to the intensive care unit (ICU) during the delta wave of the pandemic, including 12 unvaccinated patients (closed circles), and 5 fully vaccinated patients (open circles). ), and 1 patient was vaccinated and boosted (additional markers) (panel C). In addition, neutralizing antibody titers are shown for 31 patients who were hospitalized with Covid-19 but were not admitted to the ICU during the omicron wave of the epidemic, including 15 unimmunized patients (closed circles), 8 patients who were Fully vaccinated (open circles)), and 8 vaccinated and stimulated patients (plus signs) (panel D). In all cases, geometric mean values ​​of the 50% break-even titer (NT50) in the top of the plots along with the percentage of patients with neutralizing antibody titers above the detection limit (value 80), as indicated by the dashed lines. 𝙸 Bars represent 95% confidence intervals. Statistical significance was determined by one-way repeated measures analysis of variance with Bonferroni’s multiple correction. NS indicates that it is not significant.

We first examined neutralizing antibody titers in serum samples obtained from 10 healthcare workers 3 to 4 weeks after they had received the second dose of mRNA-1273 (Moderna) vaccine (in 3 workers) or BNT162b2 vaccine (Pfizer- BioNTech) (in 7 workers) (Table S1). Compared with the response against the D614G variant, neutralizing antibody titer was 3.3-fold lower against the BA.3 variant and 44.7-fold lower against the deltacron variant (P < 0.001 for both comparisons) (Figure 1a). However, after the same healthcare workers received a booster dose of the same vaccine used in the two-dose series, neutralizing antibody titer was 2.9-fold lower against the BA.3 variant and 13.3-fold lower against the deltacron variant as versus the D614G variant (P < 0.001). for both comparisons)Figure 1b). Compared with the major substrains of omicron, the deltacron variant showed similar resistance to neutralizing antibodies to the BA.1 and BA.2 variants, while the BA.3 variant (which does not contain many critical mutations in the receptor-binding domain, such as was seen in variants of BA. other omicron) was more sensitive to both doses and booster samples obtained from healthcare workers (Fig. S2A, S2B and S2C).

We then examined neutralizing antibody titers in serum samples obtained from 18 patients 3 days after admission to the intensive care unit (ICU) during the delta wave of the epidemic (Table S1). Of these, 12 patients were unvaccinated, 5 were fully vaccinated, and one was vaccinated and booster. These patients had similar titers of neutralizing antibodies versus the D614G and BA.3 variants. However, the titers versus the deltachron variant were 137.8 times lower than the titers versus the D614G variant, with only 44.4% of patients having antibody-neutralizing titers versus the deltachron variant that was above the detection limit (Figure 1c). Again, the escape of neutralization of the deltacron variant was parallel to that of the BA.1 and BA.2 variants, while the BA.3 variant remained highly sensitive to neutralization (Fig. S3A, S3B and S3C). The six vaccinated patients had significantly higher titer versus the D614G and BA.3 variants than the unvaccinated patients, whereas the deltacrine variant largely escaped neutralization.

Finally, we examined serum samples obtained from 31 patients who were hospitalized during an omicron wave but not admitted to the ICU (Table S1). We observed that the neutralization of the deltacron and BA.3 variants was similar to that of the D614G variant, with the titers being much lower than those in the samples obtained during the delta wave (Figure 1d). The neutralization of both deltacron and BA.3 variants was similar to that of BA.1 and BA.2 variants; The delta variant had the most serum resistance obtained during the omicron wave (Fig. S3D, S3E and S3F). This similar neutralization of omicron sublines occurred regardless of vaccination status, with 8 patients receiving two doses and 8 patients receiving three doses. It is important to note that patients who were hospitalized during an omicron wave had broader neutralization of all tested omicron variables than those who were hospitalized during a delta wave (Fig. S3A and S3D). On average, health care workers who received three doses of the vaccine had stronger and broader immunity than patients evaluated during an omicron wave regardless of vaccination status, with neutralizing antibody titers versus the D614G variant being 59.9 times higher as Case in patients during the omicron wave. Furthermore, the booster health care workers had an antibody neutralizing titer against the D614G variant that was 4.2 times higher than those among the health care workers who received two doses of the vaccine and 2.8 times higher than that among patients evaluated during Treatment period. delta wave.

Overall, our results indicate that BA.3 is not an intrinsic immune escape variant, a finding likely due to the lower number of mutations in the receptor-binding domain compared to the BA.1 and BA.2 variants. However, the deltacron variant retains the strong resistance of other omicron sublines and does not have an enhanced sensitivity to serum obtained during the delta wave. Although the effect of delta-derived spike mutations in the N-terminal domain on virus replication and pathogenesis remains unclear, these mutations do not appear to impair neutralization resistance. Recombination of SARS-CoV-2 variants and the potential emergence of a more virulent variant with strong immune escape remains a serious concern and requires continuous monitoring.

John B Evans, MS
Bunky Choo, Mrs.
Kong Zeng, Ph.D.
Yi Min Zheng, MD
Claire Carlin
Joseph S. Bednach, MD
Gerard Lozansky, MD
Rama K. Malambali, MD
Linda C. Seif, Ph.D.
Eugene M. Oltz, Ph.D.
Peter J. Mohler, Ph.D.
Richard C. Jumina, MD, PhD.
Shan Lu Liu, MD, PhD.
Ohio State University, Columbus, Ohio
[email protected]

Supported by funding from a private donor to Ohio State University (for Dr. Liu); Via Award (U54CA260582, to Drs. Liu, Lozanski, Gumina, Saif and Oltz) from National Cancer Institute National Institutes of Health (National Institutes of Health); Grant (R01 AI150473, to Dr. Liu) from National Institutes of Health; a Glenn Barber Fellowship (To Mr. Evans) of The Ohio State University College of Veterinary Medicine; Grants (to Dr. Jumina) from Robert J. Fund. Anthony Cardiovascular Research and the JB . Cardiovascular Research Fund; Grant (R01 HD095881, to Dr. Seif) from National Institutes of Health; Grants (UL1TR002733 and KL2TR002734 to Dr. Bednash) from National Center for the Development of Translational Sciences.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

The opinions expressed in this letter are those of the authors and do not necessarily reflect the official opinions of the National Institutes of Health.

This message was posted on May 18, 2022, at NEJM.org.

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2022-05-18 21:03:13

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