Immune evasiveness of SARS-CoV-2 variants and vaccine selection
Authors: Malin Inghammar, Fredrik Kahn
Journal: The Lancet Infectious Diseases (2024)

The constant transformation of SARS-CoV-2 poses considerable challenges for COVID-19 vaccine programmes. Since it was first detected in August, 2023, the SARS-CoV-2 omicron subvariant BA.2.86, and in particular the sublineage JN.1, have rapidly spread around the world. Compared with the subvariant XBB, BA.2.86 has more than 30 mutations in the spike protein, and its descendant JN.1 harbours an additional crucial mutation, Leu455Ser, in the angiotensin-converting enzyme 2 binding domain.1Wang Q Guo Y Liu L et al.Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike.Nature. 2023; 624: 639-644Crossref PubMed Scopus (32) Google Scholar, 2Yang S Yu Y Xu Y et al.Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure.Lancet Infect Dis. 2024; 24: e70-e72Summary Full Text Full Text PDF PubMed Google Scholar WHO classified JN.1 as a variant of interest shortly after its detection, and justified concern has been raised about whether the XBB.1.5 updated vaccine would provide effective protection against this new subvariant.3Qu P Xu K Faraone JN et al.Immune evasion, infectivity, and fusogenicity of SARS-CoV-2 BA.2.86 and FLip variants.Cell. 2024; 187: 585-595.e6Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar In The Lancet Infectious Diseases, Moustsen-Helms and colleagues4Moustsen-Helms IR Bager P Larsen TG et al.Relative vaccine protection, disease severity, and symptoms associated with the SARS-CoV-2 omicron subvariant BA.2.86 and descendant JN.1 in Denmark: a nationwide observational study.Lancet Infect Dis. 2024; (published online May 15.)https://doi.org/10.1016/S1473-3099(24)00220-2Google Scholar present a clear and straightforward assessment of whether the XBB.1.5 updated vaccine has diminished protection against the subvariant BA.2.86, including JN.1. In brief, between Oct 1 and Dec 31, 2023, the authors conducted a nationwide study of more than 3800 participants aged 65 years and older in Denmark with confirmed COVID-19 and available genomic data on the infecting SARS-CoV-2 variant. 57% of participants were infected with BA.2.86, including 42% with JN.1. By including only those who tested positive for SARS-CoV-2, the authors could estimate the diminished protection of the vaccine towards the new variants without direct estimation of vaccine effectiveness, which can be difficult to estimate in an endemic situation in which testing is scarce and almost the whole population is vaccinated. Mouststen-Helms and colleagues4Moustsen-Helms IR Bager P Larsen TG et al.Relative vaccine protection, disease severity, and symptoms associated with the SARS-CoV-2 omicron subvariant BA.2.86 and descendant JN.1 in Denmark: a nationwide observational study.Lancet Infect Dis. 2024; (published online May 15.)https://doi.org/10.1016/S1473-3099(24)00220-2Google Scholar show that the adjusted odds of infection with BA.2.86, rather than a non-BA.2.86 variant, were 1·52 (95% CI 1·25–1·86) times higher among participants who had received an XBB.1.5 updated vaccine than among those who had not, implying that the protection induced by the XBB.1.5 updated vaccine is diminished against BA.2.86 and the JN.1 sublineage. Of particular interest and concern is that this finding was also observed when examining the subgroup of participants admitted to hospital because of COVID-19. However, there was no evidence for an increased risk of hospitalisation attributed to the variant itself (odds ratio [OR] 1·04; 95% CI 0·86–1·26). Before the rapid spread of BA.2.86 in October, 2023, the authors had compared the hospitalisation risk from COVID-19 in recipients of the XBB.1.5 booster with that of people who received a COVID-19 booster vaccination during the previous season.5Hansen CH Moustsen-Helms IR Rasmussen M Søborg B Ullum H Valentiner-Branth P Short-term effectiveness of the XBB.1.5 updated COVID-19 vaccine against hospitalisation in Denmark: a national cohort study.Lancet Infect Dis. 2024; 24: e73-e74Summary Full Text Full Text PDF PubMed Google Scholar In that study, the hospitalisation risk among those who did not receive the XBB.1.5 booster was 0·69 per 100 person-years at risk and the estimated vaccine effectiveness for the XBB.1.5 booster was 76%.5Hansen CH Moustsen-Helms IR Rasmussen M Søborg B Ullum H Valentiner-Branth P Short-term effectiveness of the XBB.1.5 updated COVID-19 vaccine against hospitalisation in Denmark: a national cohort study.Lancet Infect Dis. 2024; 24: e73-e74Summary Full Text Full Text PDF PubMed Google Scholar Building on these previous findings, the current study approximates the short-term vaccine effectiveness against hospitalisation due to BA.2.86, including JN.1, to be 64%.4Moustsen-Helms IR Bager P Larsen TG et al.Relative vaccine protection, disease severity, and symptoms associated with the SARS-CoV-2 omicron subvariant BA.2.86 and descendant JN.1 in Denmark: a nationwide observational study.Lancet Infect Dis. 2024; (published online May 15.)https://doi.org/10.1016/S1473-3099(24)00220-2Google Scholar On the basis of these results, the calculated number needed to vaccinate to prevent one hospitalisation before the emergence of BA.2.86 would be 189, which would increase to 226 with the arrival of BA.2.86 owing to decreased vaccine effectiveness. In the time of limited testing recommendations, all studies based on clinical sampling inclusion are likely to be skewed towards COVID-19 cases with more severe clinical presentation. Therefore, a particular strength of this study is the additional inclusion, through a population-based self-sampling surveillance programme, of patients with milder cases of COVID-19 who have not been in contact with the health-care system. Importantly, no evidence of change in the distribution of self-reported symptoms between BA.2.86 and non-BA.2.86 infections was found, although any change in the proportion of asymptomatic infections would be undetected. A few other reports have estimated the immune evasiveness of BA.2.86 separately from that of other co-circulating strains. In a prospective study from the Netherlands with self-based testing, the data similarly suggest a lower protection from the XBB.1.5 updated vaccine against BA.2.86 and JN.1 than against other circulating variants (n=407; OR 1·5 [95% CI 0·8–2·6]).6Huiberts AJ Hoeve CE de Gier B et al.Effectiveness of omicron XBB.1.5 vaccine against infection with SARS-CoV-2 omicron XBB and JN.1 variants, prospective cohort study, the Netherlands, October 2023 to January 2024.Euro Surveill. 2024; 292400109Crossref PubMed Scopus (0) Google Scholar In a 2024 report from the USA with a test-negative design, vaccine effectiveness towards symptomatic infection 60–119 days after receiving the XBB.1.5 updated vaccine was estimated to be 49% (95% CI 19–68) for individuals with probable JN.1 infections (n=258) compared with 60% (35–75) for those with probable non-JN.1 infections.7Link-Gelles R Ciesla AA Mak J et al.Early estimates of updated 2023–2024 (monovalent XBB.1.5) COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection attributable to co-circulating omicron variants among immunocompetent adults—increasing community access to testing program, United States, September 2023–January 2024.MMWR Morb Mortal Wkly Rep. 2024; 73: 77-83PubMed Google Scholar Taken together, both virological and epidemiological results so far suggest that the short-term risk of breakthrough infections from BA.2.86 is higher than that from other co-circulating variants. The continued monitoring of the evolution of SARS-CoV-2 and its immune evasiveness, and how vaccine protection wanes over time, will be important. The study by Moustsen-Helms and colleagues4Moustsen-Helms IR Bager P Larsen TG et al.Relative vaccine protection, disease severity, and symptoms associated with the SARS-CoV-2 omicron subvariant BA.2.86 and descendant JN.1 in Denmark: a nationwide observational study.Lancet Infect Dis. 2024; (published online May 15.)https://doi.org/10.1016/S1473-3099(24)00220-2Google Scholar illustrates the value of robust systems for the continuous genomic and epidemiological surveillance of SARS-CoV-2. We declare no competing interests. MI is supported by grants from the Swedish Society for Medical Research. MI and FK are supported by Swedish governmental funds for clinical research (ALF). Relative vaccine protection, disease severity, and symptoms associated with the SARS-CoV-2 omicron subvariant BA.2.86 and descendant JN.1 in Denmark: a nationwide observational studyCompared with other SARS-CoV-2 variants, BA.2.86 and the JN.1 sublineage were less sensitive to vaccine-induced immune protection from the XBB.1.5 updated COVID-19 vaccine; however, we found no evidence that infection with BA.2.86 or JN.1 resulted in increased disease severity or different symptom profiles. Although less effective against the new variants, XBB.1.5 vaccination remains protective and reduces the risk of infection and COVID-19 disease. Full-Text PDF