Since the outbreak of COVID-19 in late 2019, the SARS-CoV-2 virus has undergone significant genetic evolution, resulting in the emergence of numerous variants with varying epidemiological and clinical characteristics. Among the recent variants, JN.1, a sublineage of Omicron BA.2.86, has emerged as a notable Variant of Interest (VOI), first identified in August 2023 [1]. It has since demonstrated rapid dominance in global sequencing reports due to its enhanced transmissibility and immune escape potential [2].

The World Health Organization (WHO) classifies emerging variants into three risk-based categories: Variants Under Monitoring (VUM), Variants of Interest (VOI), and Variants of Concern (VOC). A VOI like JN.1 is characterized by mutations that influence viral transmission or clinical severity, but with limited evidence of significant global health impact compared to VOCs [3]. Despite being assessed as a low to moderate global risk, JN.1 has established itself as the most widespread VOI by early 2024, being detected in over 121 countries [4].

Epidemiological surveillance from the WHO and CDC revealed a sharp rise in JN.1’s prevalence—from 3.3% in week 44 of 2023 to 95.1% by week 13 of 2024—highlighting its superior fitness compared to other lineages [5]. Genomic data suggest that the L455S mutation in the spike protein contributes significantly to the variant’s increased infectivity and immune evasion [6]. While initial reports show no drastic increase in severity, populations with weakened immunity—particularly the elderly and those with comorbidities—remain at elevated risk [7].

Vaccination continues to offer strong protection against severe outcomes; however, the immune response to JN.1 varies depending on the vaccine type and prior infection history [8]. The global response to JN.1 includes updated mRNA vaccine boosters, antiviral therapies like Paxlovid and Remdesivir, and reinforced genomic surveillance efforts [9]. Yet, with declining vaccine uptake in many regions, JN.1’s rapid spread underlines the critical need for adaptive and sustained public health strategies [10].

1. Search Strategy

A comprehensive literature search was conducted to identify peer-reviewed studies focusing on the emergence, virological characteristics, transmissibility, clinical impact, immune evasion, and public health implications of the SARS-CoV-2 JN.1 variant. Databases searched included PubMed, Scopus, Web of Science, and MEDLINE. The search covered publications from January 2023 to April 2025. Boolean operators were used to refine results, employing combinations of the following keywords:

• “COVID-19 JN.1 variant”
• “SARS-CoV-2 BA.2.86 sublineage”
• “immune evasion”
• “transmissibility of JN.1”
• “COVID-19 vaccine efficacy 2024”
• “JN.1 clinical impact”
• “wastewater surveillance COVID-19”
• “antiviral resistance JN.1”

Reference lists of key articles were also manually searched for additional eligible studies. Only articles published in English were considered.

2.2. Inclusion and Exclusion Criteria

Studies were included if they met the following criteria:

• Focused specifically on the JN.1 variant or its parent lineage BA.2.86
• Addressed biological, epidemiological, or clinical characteristics
• Reported outcomes related to vaccine effectiveness, antiviral response, or surveillance methods
• Were original research articles, systematic reviews, meta-analyses, or official public health updates (e.g., WHO or CDC reports)

Exclusion criteria were:

• Non-peer-reviewed preprints without subsequent validation
• Opinion articles or editorials lacking primary data
• Studies focused solely on non-JN.1 Omicron sublineages unless used for direct comparison

2.3. Data Extraction

Two independent reviewers extracted data from eligible studies using a standardized template. Extracted parameters included:

• Mutation profile and viral structure
• R0 values and transmissibility data
• Hospitalization and mortality rates
• Vaccine response and breakthrough infection rates
• Antiviral therapy outcomes
• Surveillance techniques (e.g., genomic sequencing, wastewater monitoring)

Discrepancies between reviewers were resolved by consensus or a third reviewer.

2.4. Quality Assessment

The Newcastle-Ottawa Scale (NOS) was used to assess the quality of observational studies. For randomized controlled trials (RCTs), the Cochrane Risk of Bias Tool was employed. WHO and CDC technical reports were included based on relevance, authorship credibility, and data transparency. Studies rated “low” in quality or lacking methodological detail were excluded from the final synthesis.

2.5. Data Synthesis

A narrative synthesis was conducted due to heterogeneity in outcome reporting and study design. Findings were organized into the following thematic domains:

1. Virological features and mutations of JN.1
2. Epidemiological trends and global spread
3. Clinical presentation and population impact
4. Therapeutic management and vaccine response
5. Surveillance methods and containment strategies

Fig 1: A PRISMA flow diagram summarizing study selection is included in here.

3.1 Study Selection and Scope

A total of 50 eligible studies were included after screening 142 records identified through the database search Fig 1. These studies spanned five major regions and covered a wide range of topics, from genomic surveillance to therapeutic effectiveness. The distribution of studies by geographical region and their primary focus is summarized below in Table 1.

Table 1. Distribution of Studies by Region and Focus

3.2 Virological and Molecular Findings

Genomic sequencing revealed that the JN.1 variant contains multiple mutations in the spike protein, especially within the receptor-binding domain (RBD), contributing to immune evasion and altered host cell interaction. Notably, the L455S and S456L mutations were repeatedly associated with reduced vaccine neutralization capacity. Table 2 outlines the most impactful spike mutations observed in JN.1 and their implications. Table 2

Table 2. Key Mutations in JN.1 and Their Functional Impact

3.3 Clinical and Epidemiological Characteristics

Across studies, the JN.1 variant demonstrated a reproduction number (R0) of approximately 1.8, notably higher than that of its parent lineage BA.2.86. Hospitalization and ICU admission rates also increased compared to prior Omicron sublineages. Despite high transmission, the case fatality rate remains slightly lower than BA.1, likely due to accumulated population immunity. Table 3 summarizes these key clinical metrics.

Table 3. Summary of Clinical and Epidemiological Indicators

The emergence of the SARS-CoV-2 JN.1 variant represents a critical turning point in the COVID-19 pandemic’s evolutionary trajectory. With its origin in the BA.2.86 Omicron lineage, JN.1 has rapidly established dominance, largely due to its unique spike protein mutations such as L455S and S456L, which facilitate both increased ACE2 binding affinity and immune evasion [11]. These features contribute to a notable rise in transmissibility and a reduction in vaccine-induced neutralization capacity, posing new challenges to global public health strategies [12].

Recent epidemiological trends show that JN.1 reached a prevalence of over 95% in global genomic sequences by March 2024, a level of dominance not previously seen in other Omicron subvariants [13]. Notably, while the case fatality rate associated with JN.1 (0.34%) is slightly lower than earlier variants like BA.1 (0.41%), hospitalization and ICU admissions have significantly increased, especially among elderly and immunocompromised individuals [14]. This aligns with WHO’s risk assessment indicating that although JN.1 poses a low overall threat to the general population, it remains a serious concern for vulnerable groups [15].

One of the most striking features of JN.1 is its capacity to evade immunity, even among individuals who received the original three-dose vaccine regimen. Breakthrough infection rates as high as 25% have been documented in this group, compared to 17% for earlier variants such as XBB.1.16 [16]. However, encouraging data from updated mRNA vaccines targeting the XBB.1.5 spike sequence show improved neutralization responses, with up to a 27-fold increase in protective antibodies against JN.1 [17].

In terms of therapeutic interventions, first-line antivirals such as Paxlovid (nirmatrelvir–ritonavir), Remdesivir, and Molnupiravir have demonstrated continued efficacy against JN.1, provided administration begins within 5–7 days of symptom onset [18]. However, monoclonal antibody therapies—particularly those targeting the receptor-binding domain—have shown markedly reduced effectiveness, underscoring the need for revised therapeutic strategies in future waves [19].

The implications for public health policy are significant. As vaccine-induced immunity wanes and variant-specific immune escape increases, non-pharmaceutical interventions (NPIs) regain importance. Reinforced use of masks, social distancing in high-risk environments, and widespread genomic surveillance are essential to minimize transmission [20]. Moreover, public health messaging must adapt to overcome pandemic fatigue and ensure compliance with evolving guidelines.

The rapid global spread of the JN.1 variant underscores the continually evolving nature of the COVID-19 pandemic. With its origin in the BA.2.86 Omicron sublineage, JN.1 has exhibited a unique combination of heightened transmissibility and immune escape due to key spike protein mutations. Although currently classified as a Variant of Interest (VOI), its dominance across multiple regions, rise in hospitalization rates, and diminished response to earlier vaccine formulations warrant serious public health attention.

Despite a relatively stable case fatality rate, JN.1’s capacity to bypass immunity in previously vaccinated individuals—especially those not updated with bivalent or XBB-specific boosters—has led to increased breakthrough infections. Encouragingly, revised mRNA vaccines and existing oral antivirals like Paxlovid and Remdesivir remain effective when administered early in the disease course. However, the variant's resistance to monoclonal antibody therapies presents a limitation in high-risk or immunocompromised populations.

Key Recommendations:

1. Vaccination Drive Reinforcement: Boost public awareness campaigns to increase uptake of updated monovalent and bivalent boosters, especially in older adults and high-risk groups.
2. Global Genomic Surveillance: Expand the use of wastewater monitoring, GISAID data sharing, and real-time genomic sequencing to track variant shifts and hotspots.
3. Non-Pharmaceutical Interventions (NPIs): Reinstate basic NPIs like masking, hand hygiene, and ventilation in high-risk indoor settings, particularly during seasonal surges.
4. Antiviral Access and Awareness: Ensure equitable and early access to antiviral medications, and educate clinicians about early administration protocols.
5. Research and Monitoring: Invest in longitudinal studies to assess the long-term impact of JN.1, the durability of updated vaccine-induced immunity, and next-generation monoclonal antibody development.

In summary, the JN.1 variant reflects the virus’s continued ability to evolve under immunological pressure. A proactive, layered approach involving vaccination, surveillance, therapeutics, and public engagement is essential to mitigate its impact and prevent healthcare system strain.

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