Omicron infection enhances Delta antibody immunity in vaccinated persons

Abstract

The extent to which Omicron infection^1-9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3-9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19-27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement.

Fig. 1. Enhancement of Delta neutralization by Omicron infection.

a,b, Neutralization of the Omicron BA.1 virus over time for n = 15 vaccinated (a) and n = 24 unvaccinated (b) participants infected with Omicron BA.1. c,d, Neutralization of the Delta virus over time for the same vaccinated (n = 15; c) and unvaccinated (n = 24; d) participants as in a,b. For each participant, the sample collected at the initial enrolment visit (median 6 days post symptom onset) was compared with that collected at the last follow-up visit (median 23 days post symptom onset). The neutralization capacity per participant was determined in two independent experiments, and the numbers and horizontal bars are GMTs over all participants per group of the reciprocal plasma dilution (FRNT₅₀) resulting in 50% neutralization. The fold change was calculated by dividing the GMT from the follow-up by the GMT from the enrolment visit. The dashed line is the most concentrated plasma tested. The P values were determined by a left-sided Wilcoxon rank sum test measuring the significance of the increase; **P = 0.01–0.001; NS, not significant. The exact P values are 0.0012 (a), 0.0081 (b), 0.0021 (c) and 0.11 (d). Source data

Fig. 2. Gap in neutralizing immunity between vaccinated and unvaccinated participants infected with Omicron BA.1.

a, Neutralization of Omicron BA.2, Beta, Delta and ancestral (with the D614G substitution) viruses compared to the Omicron BA.1 virus at the last available follow-up time point in n = 15 vaccinated or n = 24 unvaccinated participants infected with Omicron BA.1. The neutralization capacity per participant was determined in two independent experiments, and the numbers and horizontal bars are GMT FRNT₅₀. The fold change was calculated by dividing the larger by the smaller GMT. The dashed line is the most concentrated plasma tested. The P values were determined by a two-sided Wilcoxon rank sum test; *P = 0.05–0.01; NS, not significant. The exact P values (vaccinated/unvaccinated) are: 0.22/0.087 for BA.2, 0.36/0.071 for Beta, 0.15/0.25 for Delta and 0.014/0.20 for ancestral. b, Comparison of the neutralization capacity against the Omicron BA.1, Omicron BA.2, Beta, Delta and ancestral (D614G) viruses in vaccinated (n = 15) versus unvaccinated (n = 24) participants infected with Omicron BA.1. The neutralization capacity per participant was determined in two independent experiments for all strains except for Omicron BA.1, for which six experiments were available and were used in the calculation. The points represent GMT FRNT₅₀ per group and the error bars are GMT 95% CIs. The P values were determined by a two-sided Wilcoxon rank sum test; *P = 0.05–0.01; **P = 0.01–0.001; ***P = 0.001–0.0001. The exact P values are 0.025 (BA.1), 0.0026 (BA.2), 4.1 × 10⁻⁴ (Beta), 0.0012 (Delta) and 3.3 × 10⁻⁴ (ancestral). Source data

Fig. 3. Escape of Omicron virus from Delta-infection-elicited immunity.

Neutralization of Delta compared to the Omicron BA.1 virus by Delta-infection-elicited plasma immunity in vaccinated and unvaccinated participants. A total of 18 samples were tested from n = 14 participants infected during the Delta infection wave in South Africa. The neutralization capacity per participant was determined in two independent experiments, and the numbers and horizontal bars are GMT FRNT₅₀. The fold change was calculated by dividing the larger by the smaller GMT. The dashed line is the most concentrated plasma tested. ****P = 3.2 × 10⁻⁷ as determined by a two-sided Wilcoxon rank sum test. Source data

Extended Data Fig. 1. Longitudinal Omicron/BA.1 and Delta neutralization capacity in Omicron/BA.1 infected participants.

Neutralization of Omicron (blue) and Delta (red) at all study visits. Participant number is as in Extended Data Table 1. Top three rows are participants vaccinated with Pfizer BNT162b2 (n = 8) or Johnson and Johnson Ad26.CoV2.S (n = 7) and bottom five rows are unvaccinated participants (n = 24). X-axis is the time post-symptom onset when sample was collected, and y-axis is neutralization as FRNT₅₀. Dashed line is the most concentrated plasma tested (LOQ, limit of quantification below which FRNT₅₀ values are extrapolated). All participants recovered except participant 29, who died.

Extended Data Fig. 2. Fold-drop in BA.2 versus BA.1 neutralization in all and sequence confirmed samples.

Neutralization of Omicron BA.2 compared to BA.1 in participants described in Extended Data Table 1, excluding participant 14 for technical reasons and participants 40 and 41 because of advanced HIV disease. Left panel shows neutralization capacity in all n = 38 participants and right panel shows neutralization capacity for n = 25 participants where infection was successfully sequenced and determined to be BA.1. Dashed line is the most concentrated plasma tested. p-values were 0.077 for all and 0.15 for BA.1 sequence confirmed participants as determined by a two-sided Wilcoxon rank sum test. ns, not significant.