JN.1: ongoing considerations of the shifting landscape of SARS-CoV-2 variants

Keywords: :

• COVID-19
• healthcare
• mutations
• spike protein
• vaccine
• variant

The new SARS-CoV-2 variant, JN.1, casts a shadow of doubt over the hard-won progress made in combating the virus and ending the COVID-19 pandemic. JN.1 is currently categorized as a variant of interest (VOI) by the World Health Organization (WHO) [1], with the latest reports suggesting that it now accounts for 39–50% of COVID-19 cases in the USA [2]. Rising case numbers have also been observed in India, China and Singapore, with significant morbidity threat [3]. Global prevalence is still escalating with more than 40 countries continuously depositing JN.1 sequences in GISAID. WHO has designated high and moderate risks to the transmission and immune escape attributes of JN.1, respectively, and expressed concerns about the limited experiment-driven conclusions of future risks and recommendations [4]. While there is no conclusive evidence that JN.1 presents an increased risk to public health, the mortalities due to JN.1 infection should be considered a warning to monitor the ongoing occurrence of variants; current diagnostic tests (RT-PCR) show efficacy in the detection of JN.1 and preliminary investigations also suggest that the present treatment line for COVID-19 will be effective against JN.1 infection [3], however, the transmissibility, virulence and immune evasion mechanisms of JN.1 are still under scrutiny.

The new variant, JN.1 (or BA.2.86.1.1), was first identified in August 2023 as a closely related variant of the BA.2.86 lineage of SARS-CoV-2 [3]. The lineage is phylogenetically distinct from the circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. BA2.86 has a significantly high potential for immune invasion attributed to more than 30 mutations in the spike (S) protein [3,5]. Other mutations have been found in the M protein, the N protein, ORF 7b, NSP2, NSP3, NSP6 and NSP9. JN.1 bears three unique mutations – L455S in S protein, R252K in NSP6 and F19L in ORF7b – while the others are similar/closely related to the ancestor strain BA.2.86.1. Current speculation is that the increased transmissibility and immune escape ability of JN.1 might be attributed to the L455S mutation in the S protein; the reproductive number of JN.1 calculated from multi-nation genomic surveillance data was found to be higher than BA.2.86.1 and HK.3 [5] and there is a minor difference in the interaction of JN.1 with the ACE2-receptor as a result of the L455S, although the overall antigenicity is conserved. Neutralization titers and molecular assays have also indicated improved immune evasion and resistance of JN.1 against monovalent XBB.1.5 vaccine sera, as compared with ancestral strains. The F19L mutation in the otherwise conserved structural protein ORF7b is also of interest, since this protein plays an important role in eliciting immune responses in the host [5,6].

A study has recently hinted to significantly low sera neutralizing titers against BA.2.86 and JN.1, demonstrating that population-level immunity established by vaccinations or infections is diminishing [7]. This may increase the risk of reinfection, especially over the winter months in the northern hemisphere. However, the increase in JN.1 cases may not be due to weaker immunity, but rather increased viral transmissibility and infectivity [7]. Very recently, Yang et al. investigated the humoral immune evasion of JN.1 following three doses of vaccinations in two cohorts: those who experienced XBB lineage breakthrough infections after immunization and those recovering from XBB lineage breakthrough infections [8]. Immune escape was significantly enhanced for JN.1 compared with BA.2.86, with a two- to onefold decrease in neutralization titers. JN.1 was also able to evade plasma better than competing variants HV.1 (EG.5 + L452R) and JD.1.1 (FLip + A475V). Structural analytics showed a significant decrease in ACE2 binding affinity with the JN.1 receptor binding domain, owing to the presence of L455S at the binding interface, suggesting its enhanced immune escape capabilities. The L455S mutation also improved JN.1's resistance to class 1, 2 and 3 antibodies, hence overcoming the survival limitations of BA.2.86, HV.1 and JD.1.1. This evolved ‘intelligence’ can be attributed to the genetic information accumulated from the ancestral strains with high human ACE2 binding affinity and distinct antigenicity, such as BA.2.86 and BA.2.75, despite their unimpressive immune evasion capabilities (a phenomenon like earlier BA.2.75 to CH.1.1 and XBB transitions). Owing to antigenic diversity, these strains can target different populations and potentially accrue highly immune-evading mutations at the expense of human ACE2 binding capabilities, allowing them to persist and spread [8,9]. In order to better understand the possible consequences of immune escape, WHO and its Technical Advisory Group on SARS-CoV-2 Evolution (TAG-VE) have recommended that member states should prioritize measures to monitor antibody escape and severity concerns related to BA.2.86 and JN.1. The recommended timelines and approximations will vary across nations based on immunization status. Neutralization assays using JN.1 live virus isolates and human sera are recommended for 2–4 weeks, while comparative analysis is recommended for 4–12 weeks [4].

In terms of potential solutions, it should be noted that although S-protein concentrating vaccines have shown high universal efficacy, the vulnerability of the S protein to mutation should not be ignored. Targeting humoral and T-cell immunity, as well as innate immunity, is an important consideration in light of variants with numerous mutations in the S protein. Vaccinations should also induce polyclonal responses against a variety of epitopes, in addition to the polyfunctionality of vaccine-induced antibodies and T-cells. Mutations altering the structural patterns might also challenge the existing S-protein targeted vaccines [10,11]. Thorough post-implementation surveillance of vaccine effectiveness and a thorough analysis of vaccine failures will be essential. For example, surveillance and testing can offer useful insights into the genetic similarities and differences of isolates from individuals infected after or without vaccination. SARS-CoV-2 variants have challenged the notion that the slow mutation rate of betacoronaviruses might ‘buy time’ for designing sustainable vaccines or therapeutic interventions [12]. Considering the slow but steady evolution in past decades and the ability to acquire favorable mutations for enhanced survival and infectivity, continuous genetic surveillance of coronaviruses is important to determining the future of vaccines. Automated data-scraping and high-quality genomic surveillance of JN.1 can guide early laboratory-based and computer-modelled studies predicting immune escape and outbreak preparedness, besides understanding the lineage's broad geographic distribution for future implications [13].

The immune evasion of newer variants has further shifted the focus on existing vaccination shortcomings, similar to those against non-systemic respiratory viruses like influenza. These viruses are characterized by seasonal outbreaks and re-infections, owing to short-lived immunity in hosts. The viruses replicate quickly and require less time to incubate, primarily in local mucosal tissue, without interacting sufficiently with the systemic immune system or the full force of adaptive immune responses. With similar behaviour, SARS-CoV-2 tends to re-infect individuals multiple times during their lives without ever producing total and lasting immunity. Similarly to the antigenic plasticity in the S-protein resulting in the outbreak of the emerging SARS-CoV-2 variants, rapid antigenic drift results in annual influenza outbreaks, which also challenges the development of broadly protective, universal vaccines [14]. Therefore, annual flu vaccinations are adopted to mitigate seasonal outbreaks. Similarly, government and public health bodies are focusing on continuous variant monitoring and adopting annual vaccination strategies against SARS-CoV-2 to improve protection against severe outbreaks and boost waning immunity against the emerging variants. The deployment (timing and frequency) of updated COVID-19 vaccines will depend on SARS CoV-2's seasonal circulation as well as the virus' change over time [15].

Looking into other options, whole cell vaccines can trigger a more extensive and heterologous polyclonal response directed against multiple viral antigens, some of which are more genetically stable than the S-protein [16,17]. The mRNA vaccines have demonstrated effectiveness even after only one dosage, at which point there are essentially no neutralizing antibodies (Nabs) but moderate T helper cell responses and non-NAbs. The adenovirus vaccines induce powerful T-cell responses and polyfunctional antibodies that can mediate viral neutralization and trigger additional antibody-dependent effector actions after only one dose. These imply that protection might involve non-NAbs, T cells and innate immunological pathways, in addition to low concentrations of Nabs [10]. Another suggestion was to focus on developing nasal and pan–SARS-CoV-2 or pan-sarbecovirus vaccines instead of considering each emerging variant at a time. A nasal vaccine has the potential to halt SARS-CoV-2 in its tracks and prevent its spread, whereas a pan-SARS-CoV-2 or pan-sarbecovirus vaccine could elicit an immune response against both existing and future strains of the virus [18].

The rapid rise of infective JN.1 cases in densely-populated developing nations with larger unvaccinated or part-vaccinated populations, under-resourced healthcare systems or populations that have not received updated vaccinations within the year impose persistent concerns [1,19]. However, learning from the past, outbreak preparatory measures, such as rapid testing and precautionary alerts, have already been announced in nations like India [20]. It has to be understood that, unlike influenza, we do not have half a century's worth of experience to rapidly design prophylactic measures against unpredictable variants like JN.1. Therefore, to facilitate evidence-based strategies, the Centre for Disease Control and Preventions (CDC) recommends an amalgamation of diverse surveillance approaches, comprising genomic, wastewater, traveller-history and digital public health data surveillance (e.g., global repositories, news, and social media). Overcoming the existing disparities and limitations in geographic, demographic, epidemiologic and clinical resources can further strengthen surveillance and prophylaxis [13].

Author contributions

S Basu and T Kayal: conceptualization, writing – original draft; P Prasad Patro and A Patnaik: literature retrieval, writing – review and editing.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Acknowledgments

The authors would like to acknowledge the Founder Chairman, S Mahapatra, NIST and the Head, Department of Microbiology, IGGMC & H for the suggestions and support.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.