Vaccine Breakthrough Infections with SARS-CoV-2 Variants

Abstract

Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of clinical concern. In a cohort of 417 persons who had received the second dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine at least 2 weeks previously, we identified 2 women with vaccine breakthrough infection. Despite evidence of vaccine efficacy in both women, symptoms of coronavirus disease 2019 developed, and they tested positive for SARS-CoV-2 by polymerase-chain-reaction testing. Viral sequencing revealed variants of likely clinical importance, including E484K in 1 woman and three mutations (T95I, del142-144, and D614G) in both. These observations indicate a potential risk of illness after successful vaccination and subsequent infection with variant virus, and they provide support for continued efforts to prevent and diagnose infection and to characterize variants in vaccinated persons. (Funded by the National Institutes of Health and others.).

Figure 1. Evidence of Vaccine Efficacy in Patient 1.

Panel A shows the results of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudotype neutralization assay in Patient 1. Relative luminescence units (RLUs) normalized to units from unvaccinated persons are shown. The 𝙸 bars indicate 95% confidence intervals. Panel B shows the neutralizing antibody titers in serum obtained from recovered patients 1.3 months and 6.2 months after infection, from persons who had received both doses of either the mRNA-1273 or BNT162b2 vaccine, and from Patient 1 (after vaccination and infection). The 50% neutralization testing (NT₅₀) titer among recovered patients at 1.3 months after infection did not differ significantly from that among persons who received both doses of either mRNA-1273 or BNT162b2 vaccine. The red bars indicate geometric means; high levels of neutralizing activity (mean [±SD] NT₅₀, 3209±760) in Patient 1 are shown. The mean serum neutralizing antibody titers are from three independent experiments, each performed in duplicate. NS denotes not significant.

Figure 2. Phylogenetic Tree.

In the clade analysis for Patient 1, the closest match was between clades 20B and 20C. The SARS-CoV-2 variant first identified in the United Kingdom (B.1.1.7) is clade B, and the variant first identified in New York City (B.1.526) is clade 20C.

Figure 3. Phylogenetic Comparisons of SARS-CoV-2 Variants.

The red line indicates Patient 1.

Figure 4. Neutralization Assays for Antibodies to the Wuhan-Hu-1 Isolate, the E484K Variant, and the B.1.526 Variant.

Pseudotype neutralization assays for the wild-type (Wuhan-Hu-1 isolate) virus, the E484K mutant, and the B.1.526 variant first identified in New York City (including the substitutions L5F, T95I, D253G, E484K, D614G, and A701V) were performed with a serum sample obtained from Patient 1. Shown are means and standard deviations (𝙸 bars) of three independent experiments. The E484K substitution alone or together with other substitutions in the B.1.526 variant were not significantly more resistant to neutralization by the serum from Patient 1 than the wild-type virus.