Elevated neutralization of Omicron with sera of COVID-19 recovered and breakthrough cases vaccinated with Covaxin than two dose naïve vaccinees

Dear Editor,

Yang et al., recently reported the neutralization potential of inactivated vaccines amongst breakthrough cases and vaccinees with regular and booster doses against Omicron variant.¹ The recent emergence of heavily mutated Omicron variant has swamp the world with increased number of COVID-19 infections. Though Omicron doesn't cause severe disease, it has the ability to rapidly spread and evade the immune response.² The global public health experts are mainly concerned about the immune escape potential of the Omicron. The immune response generated against COVID-19 vaccines available under emergency user authorization and natural infection with earlier variants has been found to wane over time. This essentially provides little protection against the newly emerging variants with immune escape potential such as Omicron and led to breakthrough infections and reinfections.3, 4, 5, 6, 7, 8 Andrews et al., recently reported that the individuals vaccinated with two doses of BNT162b2 or ChAdOx1 nCoV-19 vaccine didn't develop symptomatic disease upon infection with variant. Beside this, booster of any of these vaccines significantly increased protection in vaccinees which unfortunately waned over time.⁸ Covaxin, an indigenously developed inactivated COVID-19 vaccine has been used under national vaccination program in India. Till date, millions of doses have been administered to adult population in India. Considering, the impact of third wave of pandemic aroused with Omicron in India, it triggered us to study the effectiveness of Covaxin against Omicron variant. Here, we assessed the sera of naïve, recovered and breakthrough cases vaccinated with Covaxin for its neutralizing ability against Omicron variant.

The study subjects were categorized into three groups i.e., COVID-19 naïve individuals vaccinated with two doses of Covaxin (n = 52) with average age of 41.7 years (range 23–65), COVID-19 recovered cases vaccinated with two doses of Covaxin (n = 31) with average age of 41.7 years (range 26–64) and breakthrough cases post two dose vaccination with Covaxin (n = 40) with average age of 43.7 years (range 27–67). The sera samples of naïve, recovered and breakthrough cases were collected on average 97, 99 and 110 days, respectively. The breakthrough infection found to occur on average 43 days post second vaccination. Majority of the breakthrough cases presented with mild disease (95%) and two were asymptomatic (5%); while 32.5% had co-morbidities like diabetes, hypothyroidism, hypertension, cardiac arrhythmias and allergic asthma (Fig. 1 ). The IgG antibody response in serum samples of all the subjects were assessed with S1-RBD, N protein and whole inactivated antigen ELISA and the neutralizing antibody titres were determined against Omicron, Delta and Beta variant compared to the prototype B.1 variant with plaque reduction neutralization test (PRNT). ^{9 , 10}

Fig. 1.

Overview of the study design and the participants.

The PRNT50 Geometric mean titre (GMT) of the sera of COVID naïve, recovered and breakthrough cases were determined against B.1 [61.9 (95% CI, 40–96), 126.7 (95% CI, 69–232), 235.6 (95% CI, 126–440)]; Beta (12.6 (95% CI, 6–26), 49.9 (95% CI, 25–99), 66.3(95% CI, 28–157)]; Delta [30.1 (95% CI, 16–58), 79.2 (95% CI, 45–140), 154.1 (95% CI, 61–390)] and Omicron (4.9 (95% CI, 2–10), 15.9 (95% CI, 6–40), 26.6 (95% CI, 14–50)]. The GMT values were found to be decreasing with Delta, followed by Beta and Omicron variant in all the three groups. Comparative analysis of COVID naïve cases demonstrated fold-reduction of 4.9, 2.06 and 12.49 against Beta, Delta, and Omicron, respectively compared to prototype strain B.1. Similarly, reduction in the neutralizing antibody (NAb) titre was observed with sera of recovered and breakthrough cases against Delta (1.60, 1.53), Beta (2.54, 3.55) and Omicron (7.98, 8.84), respectively with parental virus (Fig. 2 A–C). A strain-wise comparative analysis of the recovered and breakthrough cases compared to 2 dose vaccinated cases demonstrated higher neutralization for former scenario (Fig. 2D–G) which were also statistically significant. A two tailed Kruskal Wallis test was used to compare the cases with different strains. Breakthrough cases had highest neutralizing activity against all the variants demonstrating significant increase in the immune response post infection. The recovered cases also showed significant immunity boost post vaccination, but were lower than the breakthrough cases. Apparently, the naïve cases had very low neutralizing titres demonstrating the waning immunity post three months of the second dose. The Omicron variant has shown a pronounced resistance to neutralization with the sera of all the three groups compared to B.1, Beta and Delta variant. The IgG antibody response evaluated with S1-RBD, N-protein and inactivated whole antigen ELISA also demonstrated increasing pattern of GMT titres in recovered (760, 594, 205), naïve (797, 758, 150) and breakthrough cases (2573, 1770, 447), respectively (Fig. 2H–J).

Fig. 2.

Plaque reduction neutralization test titer and ELISA titer of sera of COVID naïve, recovered and breakthrough cases: Dot and line plot depicting the plaque reduction neutralization test of the individual sera vaccinated with (A) two doses of Covaxin (B) recovered and two dose Covaxin (C) breakthrough cases. Strain wise scatter plot of the different vaccinated cases (D) prototype B.1 (E) Beta, (F) Delta and (G) Omicron. ELISA titer of the individual sera vaccinated with different vaccinated cases against (H) S1-RBD (I) N protein (J) Whole inactivated virion. A two-tailed pair-wise comparison was performed using the Kruskal Wallis test with a p-value of 0.05. The dotted line on the figures indicates the limit of detection of the assay. Data are presented as geometric mean titer values with 95% confidence interval.

The GMT titres of IgG and NAb clearly demonstrate highest immune response amongst breakthrough cases followed by recovered and naïve cases. Omicron was less effectively neutralized with the sera of naïve cases (12.9 fold) than recovered (7.98 fold) and breakthrough (8.84 fold) compared to B.1 (Fig. 2A–C). Although, the immune response was less against the Omicron, it would still protected the individuals from developing severe disease, hospitalization and mortality.

It is well known that the higher humoral and cellular immune response helps the people to protect from getting seriously ill with SARS-CoV-2. Recently, Vadrevu et al., reported persistent humoral and cellular immune response in individuals vaccinated with two doses of Covaxin against B.1, Alpha, Beta, Delta and Delta plus variants. Besides this, increased NAb response and protection was demonstrated with booster dose of Covaxin.¹¹ Hence, the administration of booster or precautionary dose is of much significance as it provides better protection against COVID-19 disease.

Funding

Financial support was provided by the Indian Council of Medical Research (ICMR), New Delhi at ICMR-National Institute of Virology, Pune under intramural funding ‘COVID-19′.

Declaration of Competing Interest

Authors do not have a conflict of interest among themselves.