RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
In the study, Kimura et al. studied the infectivity and immune resistance of the Lambda variant (C.37 in PANGO) using HIV-1-based reporter pseudovirus assays. They claim that the Lambda variant is highly infectious even comparable to the Delta variant (B.1.617.2 in PANGO) and potentially escaping from BNT162b2 due to L452Q, F490S, and 246_253delinsN (RSYLTPGD246-253N in the manuscript). Furthermore, the Lambda variant has exhibited vulnerability against infection-enhancing antibodies targeting the N-terminal domain.
The authors used a spike protein characterized with 7 mutations, namely, G75V, T76I, L452Q, F490S, D614G, T859N, and a deletion, 246_253delinsN. Nearly 80% of the Lambda variant, or the strain classified under C.37, harbor 246_253delinsN; therefore, the insertion should be considered as an essential constituent to the strain characterizing Lambda. Recently, Tada et al1. and Acevedo et al2. released a similar study; however, they incorrectly used a mutated spike protein with 246_252del, which is missing D253N, rather than 246_253delinsN. Both Tada et al. and Acevedo et al. reach similar conclusions—that neutralization against the Lambda variant is compromised. Yet, they did not observe any contribution from 246_253del. On the contrary, Kimura et al. demonstrated 246_253delinsN has a significant contribution to the vaccine escaping capacity of Lambda strain against BNT162b2 vaccines.
Figure 2A and S2A indicate that the Alpha (B.1.1.7) and Beta (B.1.351) variants have significantly less infectivity, which contradicts the epidemiological observation that the Alpha variant overwhelmed predecessor D614G strains and became dominant in many parts of the world. Spike protein is not the only contributing factor to infectivity and transmissivity; however, N501Y is known to increase binding with ACE23 and the reproduction number in many countries exceeded that of the predecessor strains harboring D614G4. Even compared with the result of Acevedo et al2., the observed infectivity with respect to the D614G strain appears to be low. Therefore, the authors need to justify this phenomenon.
There are several minor issues in the manuscript. The authors were unable to share the data given the incomplete link to the data (line 699), which needs to be updated. Secondly, the estimated date of the emergence of the Lambda variant is inconsistent between the one in Figure S1 and the one in the methods section (line 766). Moreover, in Figure S2B, the authors appear to color each column representing a serum donor based on neutralization titers against different spike haplotypes. If the authors' intent is to emphasize relative neutralization titers, then they should avoid simply averaging the titers of donors and fold changes with respect to the control, the D614G strain.
Tada, T., et al., SARS-CoV-2 Lambda Variant Remains Susceptible to Neutralization by mRNA Vaccine-elicited Antibodies and Convalescent Serum. bioRxiv, 2021: p. 2021.07.02.450959.
Acevedo, M.L., et al., Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda. medRxiv, 2021: p. 2021.06.28.21259673.
Starr, T.N., et al., Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. bioRxiv : the preprint server for biology, 2020: p. 2020.06.17.157982.
Davies, N.G., et al., Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science, 2021. 372(6538): p. eabg3055.