Effectiveness of ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection during the delta (B.1.617.2) variant surge in India: a test-negative, case-control study and a mechanistic study of post-vaccination immune responses

Abstract

Background: SARS-CoV-2 variants of concern (VOCs) have threatened COVID-19 vaccine effectiveness. We aimed to assess the effectiveness of the ChAdOx1 nCoV-19 vaccine, predominantly against the delta (B.1.617.2) variant, in addition to the cellular immune response to vaccination.

Methods: We did a test-negative, case-control study at two medical research centres in Faridabad, India. All individuals who had a positive RT-PCR test for SARS-CoV-2 infection between April 1, 2021, and May 31, 2021, were included as cases and individuals who had a negative RT-PCR test were included as controls after matching with cases on calendar week of RT-PCR test. The primary outcome was effectiveness of complete vaccination with the ChAdOx1 nCoV-19 vaccine against laboratory-confirmed SARS-CoV-2 infection. The secondary outcomes were effectiveness of a single dose against SARS-CoV-2 infection and effectiveness of a single dose and complete vaccination against moderate-to-severe disease among infected individuals. Additionally, we tested in-vitro live-virus neutralisation and T-cell immune responses to the spike protein of the wild-type SARS-CoV-2 and VOCs among healthy (anti-nucleocapsid antibody negative) recipients of the ChAdOx1 nCoV-19 vaccine.

Findings: Of 2379 cases of confirmed SARS-CoV-2 infection, 85 (3·6%) were fully vaccinated compared with 168 (8·5%) of 1981 controls (adjusted OR [aOR] 0·37 [95% CI 0·28-0·48]), giving a vaccine effectiveness against SARS-CoV-2 infection of 63·1% (95% CI 51·5-72·1). 157 (6·4%) of 2451 of cases and 181 (9·1%) of 1994) controls had received a single dose of the ChAdOx1 nCoV-19 vaccine (aOR 0·54 [95% CI 0·42-0·68]), thus vaccine effectiveness of a single dose against SARS-CoV-2 infection was 46·2% (95% CI 31·6-57·7). One of 84 cases with moderate-to-severe COVID-19 was fully vaccinated compared with 84 of 2295 cases with mild COVID-19 (aOR 0·19 [95% CI 0·01-0·90]), giving a vaccine effectiveness of complete vaccination against moderate-to-severe disease of 81·5% (95% CI 9·9-99·0). The effectiveness of a single dose against moderate-to-severe disease was 79·2% (95% CI 46·1-94·0); four of 87 individuals with moderate-to-severe COVID-19 had received a single dose compared with 153 of 2364 participants with mild disease (aOR 0·20 [95% CI 0·06-0·54]). Among 49 healthy, fully vaccinated individuals, neutralising antibody responses were lower against the alpha (B.1.1.7; geometric mean titre 244·7 [95% CI 151·8-394·4]), beta (B.1.351; 97·6 [61·2-155·8]), kappa (B.1.617.1; 112·8 [72·7-175·0]), and delta (88·4 [61·2-127·8]) variants than against wild-type SARS-CoV-2 (599·4 [376·9-953·2]). However, the antigen-specific CD4 and CD8 T-cell responses were conserved against both the delta variant and wild-type SARS-CoV-2.

Interpretation: The ChAdOx1 nCoV-19 vaccine remained effective against moderate-to-severe COVID-19, even during a surge that was dominated by the highly transmissible delta variant of SARS-CoV-2. Spike-specific T-cell responses were maintained against the delta variant. Such cellular immune protection might compensate for waning humoral immunity.

Funding: Department of Biotechnology India, Council of Scientific and Industrial Research India, and Fondation Botnar.

Figure 1

Study flow diagram

Figure 2

Titres of neutralising antibodies targeting wild-type SARS-CoV-2 and variants in plasma from ChAdOx1 nCoV-19 vaccine recipients Neutralisation titres estimated by focus reduction neutralisation test are plotted in log-scale on the y-axis. The dots represent neutralisation titres of individual participants (n=49). The solid black line with error bars indicate geometric mean titres and 95% CIs. The sample numbers, geometric mean titre values, and fold change in titres between the variants of concern are shown in the appendix (p 12).

Figure 3

T-cell immune responses against spike antigens of wild-type and delta variant SARS-CoV-2 in samples from vaccinated participants IFNγ (A), IL-2 (B), and IFNγ (C) concentrations in culture supernatant of peripheral blood mononuclear cells stimulated with peptide pools of wild-type and delta variant spike protein for 48 h (n=48; 47 of 48 samples responded to stimulation). Intracellular cytokine staining for IFNγ (D), IL-2 (E), and TNFα (F) in CD4 cells, and granzyme B (G), IFNγ (H), and perforin (I) in CD8 cells stimulated with peptide pools of wild-type and delta variant spike protein for 18–20 h; graphs show the proportions of cells expressing these molecules (n=41). Activation-induced marker assay of CD4 T cells (J) and CD8 T cells (K) stimulated with peptide pools of wild-type and delta variant spike protein for 24 h; graphs show the proportions of cells expressing these activation markers (n=38). (L) Antigen-specific activation of T cells by peptide pools exclusively covering the mutant regions of the delta variant spike protein compared with the homologous wild-type reference peptide pool (n=19; 19 of 24 samples responded to simulation; mean 63·78 SFCs/10⁶ PBMCs for wild-type, and 45.68 SFCs/10⁶ PBMCs for the delta variant). Each datapoint represents the readings from the peptide pool-stimulated wells for one study participant, after subtraction of the dimethyl sulfoxide-stimulated wells. IFNγ=interferon γ. SFCs=spot forming cells. TNFα=tumour necrosis factor α.