Worldwide SARS-CoV-2 Omicron variant infection: Emerging sub-variants and future vaccination perspectives

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has sparked widespread concern globally, particularly with the Omicron variant and its sub-lineages emerging as the predominant cause of infection for nearly two years. Taiwan’s successful containment of COVID-19, underscored by broad vaccine coverage, the utilization of anti-viral therapeutics, and timely response strategies, has resulted in reduced excess mortality. Moreover, there is a crucial need for a phased exit strategy, balancing efforts to curtail disease transmission with the mitigation of socioeconomic impacts from rigorous measures. In this review, we examined the evolution and the epidemiological landscape of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sub-variants in Taiwan as well as other countries of the world. We also critically evaluated the effectiveness of COVID-19 vaccines against various SARS-CoV-2 variants. Additionally, we addressed the advantages of heterologous immunization strategies, fluctuations in neutralizing antibody titers, and complexities in establishing protective correlates among swiftly mutating viral variants.

Introduction

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 760 million people, with more than 6 million fatalities.¹ After three years of unprecedented disruption of daily life, the World Health Organization (WHO) announced on May 5, 2023, an end to the global health emergency designation of COVID-19. While this announcement marked the official commencement of the post-pandemic era and the conclusion of the emergency phase, it should be noted that COVID-19 has not been eradicated.² To most public health and frontline physicians, entering the post-pandemic era has not entailed the dismantling of the COVID response systems altogether but easing the epidemic prevention measures stepwise; that is, building up an exit strategy based on updated pandemic epidemiology. Here, we conducted a comprehensive review of the current evolutionary trends of SARS-CoV-2 Omicron sub-variants, along with their epidemiology in Taiwan, and compared them with other countries facing similar conditions. We also address the current and future perspectives on COVID-19 vaccination strategies.

Evolutionary trajectory of the SARS-CoV-2 Omicron variant

SARS-CoV-2, similar to other coronaviruses, harbors a sizable RNA genome comprising roughly 30,000 nucleotides, whose replication is mediated by RNA-dependent RNA polymerase (RdRP) and an exoribonuclease (ExoN) proofreading enzyme.³ The virus’s rate of evolution is largely determined by its mutation and substitution rate, which for SARS-CoV-2, are below the range typical of other RNA viruses, such as influenza virus (approximately 1.5 × 10⁻⁵ mutations per nucleotide per replication cycle) and human immunodeficiency virus (approximately −10⁻⁴ × 10⁻⁶ mutations per nucleotide per replication cycle). The mutation rate for SARS-CoV-2 falls in the range of 1×10⁻⁶ to 2×10⁻⁶ mutations per nucleotide per replication cycle, while the substitution rate is approximately 2×10⁻⁶ per site per day, equating to nearly two evolutionary changes per month.^4–6 In conventional viral evolution, Darwinian fitness, which is heavily dependent on context and varies over time and environment, drives the process. During the early stages of the pandemic, SARS-CoV-2 was more prone to increased transmissibility and host adaptation (Fig. 1). For example, the D614G mutation, one of the earliest significant mutations, was a successful selection for an increased affinity between the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor.^7–9 Similarly, later variants of concern (VOCs) also acquired host adaptation through different mechanisms, such as an increased furin cleavage site at the S1-S2 junction in the Delta variant and an altered cell entry pathway in the Omicron variant.^10–12 However, in contrast to any previous global pandemic, the rapid development of pathogen-specific therapeutic agents and vaccines has led to diverse survival pressures on the virus. This has led to mutations that help evade the immune response, gradually replacing host adaptation and becoming one of the dominant factors driving the reproductive fitness of SARS-CoV-2 (Fig. 1). The D614G mutation in the spike protein was observed as a single, universally prevalent mutation in February 2020, the first year of the COVID-19 pandemic. The Alpha (B.1.1.7) variant was first sequenced in the United Kingdom in September 2020 and became the dominant circulating variant in December 2020.¹³ Subsequently, the Beta (B.1.351) variant identified in South Africa, Gamma (P.1) in Brazil, and Delta (B.1.617.2) in India emerged after the Alpha (B.1.1.7) variant in late 2020.^{14, 15} Delta (B.1.617.2) variant quickly became the main circulating variant throughout the world, until Omicron (B.1.1.529) took its place in the late 2021.¹⁶

Figure 1.

Evolutionary path of SARS-CoV-2. The phylogenetic trajectory of SARS-CoV-2 since January 2020 has been marked by the emergence of distinct variants, ranging from Alpha to Omicron. This evolution has transpired concurrently with advancements in anti-viral therapeutics, monoclonal antibody therapies, and vaccine development. This dynamic scenario reflects an ongoing tension between the virus’s propensity for host adaptation and the simultaneous efforts toward immune evasion.

The Omicron variant was first identified in South Africa, and the WHO called the Omicron variant the fifth VOC on November 26, 2021.^{17, 18} Omicron and its sub-variants have consistently held the position of the predominant SARS-CoV-2 strains globally for nearly two years. The Omicron variant did not originate from earlier VOCs but followed its unique evolutionary trajectory.^18–20 The Omicron variant comprises several sub-lineages with distinct transmission dynamics, dominating during different periods of the pandemic. Initially, BA.1 emerged as highly prolific, demonstrating a significant growth rate and establishing dominance in numerous regions.²¹ It harbored a substantial number of mutations, encompassing 35 in its spike protein, thereby contributing to both immune evasion and heightened transmissibility.^{12, 22, 23} BA.2 gradually outcompeted BA.1 globally, driven by enhanced transmissibility and unique mutations, solidifying its dominance in the COVID-19 pandemic.^24–27 The emergence of additional sub-lineages, including BA.4 and BA.5, has further influenced the dynamics of the Omicron variant, exhibiting distinct mutational patterns with potential implications for immune escape and transmission.^28–30

The Omicron variant diversified into multiple lineages before being detected, leading to the current sequential waves of the pandemic with the co-circulation of different omicron lineages. The Omicron lineages showed a complex interrelatedness, possibly including multiple intra-VOC combinations and potentially arising from populations susceptible to persistent infection.³¹ For instance, the BA.4 and BA.5 lineages have nearly identical 5’ ends of the genome up to the M gene but were largely divergent beyond this point, suggesting recent genetic recombination events.^{18, 32}

The recombination of different VOCs has also been identified since 2020, but not until the beginning of 2022, when recombinant VOCs rapidly increased. This is possible because of the high level of co-circulation between the Delta and Omicron lineages. Recombinant lineages, distinguished by the “X-” lineage prefix, have been identified in various geographic regions, such as the recombinant XE (BA.1 × BA.2) from England and recombinant XAY (BA.2 × Delta) from South Africa.^{31, 33, 34} However, it is the recombinant XBB, resulting from the recombination of BA.2.10.1.1 and BA2.75, that has gained extremely increased survival fitness and outcompeted other Omicron lineages in the past several months. Current evidence suggests that the rapid growth of XBB is attributable to its ability to evade the immune system, which in turn contributes to new waves of the pandemic worldwide. Immunogenicity studies have also shown a significant decrease in the neutralizing activity against XBB in sera from subjects with vaccination or previous infections.^35–38

The WHO is currently monitoring several SARS-CoV-2 variants, including five variants of interest (VOIs): XBB.1.5, XBB.1.16, EG.5, BA.2.86, and JN.1.³⁹ XBB.1.5 and XBB.1.16, both descendant lineages of XBB, were designated as VOIs in January and April 2023, respectively. The F486P mutation in XBB.1.5’s spike protein reduces immune evasion compared to XBB.1 but enhances infectiousness.^40–42 XBB.1.16, genetically akin to XBB.1.5, displays elevated immune escape and reduced fusogenicity due to additional E180V and K478R spike protein mutations compared to their parent XBB.1.⁴³

EG.5, a WHO-designated VOI since August 2023, features an additional F456L amino acid mutation in the spike protein compared to its parent XBB.1.9.2 sub-variant.⁴⁴ Among the EG.5 descendant lineages, the EG.5.1 sub-variants (including HV.1, HK.3, EG.5.1.1, and JG.3) carry significant additional mutations, particularly the Q52H mutation in the spike protein, providing them with a competitive advantage in terms of transmission over the original EG.5.⁴⁴ EG.5 was first reported on February 2023. Since then, there has been a steady increase in the proportion of EG.5, and then supplant XBB.1.5, and XBB.1.16 as the world’s most common sub-variant. According to the report from WHO on November 21, 2023, EG.5 viruses and their sub-variants currently represent more than half (51%) of the SARS-CoV-2 variants in global circulation.⁴⁵

BA.2.86 and its sub-lineages, including JN.1, have attained the status of a new VOI due to a consistent rise in global prevalence as of November 2023.⁴⁶ BA.2.86, a descendant lineage of BA.2, has samples collected as early as July 2023. Analysis of BA.2.86 sequences revealed 34 amino acid substitutions compared to BA.2 and 36 substitutions relative to XBB.1.5.⁴⁷ JN.1, a significant offshoot of BA.2.86, has gained prominence in global epidemiology and was first identified in the United States in September 2023. JN.1, with the additional L455S spike mutation compared to BA.2.86, shows evidence of enhanced immune fitness.⁴⁸ On December 18, 2023, JN.1 was designated as a distinct VOI, separate from its parent lineage, BA.2.86, due to its rapid increase in prevalence in recent weeks.³⁹

Clinical epidemiology in Taiwan and the importance of building an exit strategy

With its previous experience in handling the SARS epidemic in 2003, Taiwan was cautious about the emergence of SARS-CoV-2 during the early stages of the COVID-19 pandemic. Therefore, the Taiwan Center for Disease Control (CDC) has continuously conducted genetic sequencing of SARS-CoV-2, using samples from the “Severe Pneumonia with Novel Pathogens Designated Testing Institution Network” across the country. The primary sources of these samples include cases of imported infections, clusters, individuals vaccinated before diagnosis, reinfections, and cases with unclear infection sources after epidemiological investigations. Monitoring focuses on these key cases and is adjusted based on the domestic pandemic situation and public health policy needs. Additionally, daily new cases from various counties and cities nationwide are analyzed through random sampling.⁴⁹ Through the early implementation of border control measures and intensive quarantine strategies, Taiwan maintained a low incidence of COVID-19 until May 2021, when the first epidemic wave of the Alpha variant occurred.⁵⁰ This wave was efficiently controlled within three months through strict non-pharmaceutical intervention (NPI) policies with high population compliance. The Delta variant occurred in June 2021 but only caused sporadic community clusters, and no countrywide epidemic surge was recorded. However, three months after the first detection in Taiwan, the highly transmissible, immune-evading Omicron variant became predominant, circulating widely in Taiwan’s community since April 2022, causing the second epidemiological surge (Fig. 2). During the Omicron-dominant period, Taiwan experienced at least three successive waves caused by the co-circulation of BA.2, BA.5, and BA2.75/BA.5, followed by the more recent co-circulation of BA2.75/XBB. Unlike most regions where XBB soon replaced the BA lineage to become the most dominant Omicron lineage, BA2.75 and XBB cocirculated in Taiwan until July 2023. The phenomenon of delayed replacement of the dominant strains with more evasive ones was continually observed in Taiwan. Based on the Variant Proportion Data from the COVID Data Tracker from the United States CDC, EG.5 became the prominent strain (20.6% of all circulating variants) in August 2023 in the United States.⁵¹ However, according to the press release from Taiwan CDC on August 15, 2023, XBB variants were more prevalent in Taiwan, with XBB.1.16 accounting for 23%, XBB.1.5 for 20%, and EG.5 for 12% of the 172 domestic cases. However, among imported samples, EG.5 was the most prevalent strain (53%), followed by JN.1 (28%) and BA.2.86 (5%).⁵² In the United States, notably, JN.1 accounted for 44.2% of the circulating variants, with HV.1 at 22.1% in December 2023.⁵³ As of December 19, 2023, EG.5 remained the predominant local strain in Taiwan, comprising 88% of the circulating variants, while JN.1 was only at 3% of the domestic cases. However, among imported cases, EG.5 was still the main strain (53%), but JN.1 showed a significant increase (28%).⁵⁴

Figure 2.

Epidemiological curve of SARS-CoV-2 infection in Taiwan during the Omicron variant-predominant period. Up to March 1, 2023, Taiwan has experienced three waves driven by Omicron-dominant variants BA.2, BA.5, and BA2.75/BA.5. The timing of border control measures is represented by circled symbols and can be summarized as follows: (1) On July 25, 2022, Taiwan permitted foreign arrivals for volunteering, religious studies, internships, international exchanges, and vacation work; (2) on September 29, 2022, Taiwan relaxed entry restrictions, permitting visa-free arrivals from multiple countries, ending saliva screening, and introducing quadruple rapid testing; (3) on October 13, 2022, Taiwan reduced quarantine to 0–7 days, allowed asymptomatic passengers on public transport, lifted group limitations, and permitted non-visa-free general entry and tourism; and (4) on December 10, 2022, the upper limit on the number of people entering and leaving the country was abolished. The timing of anti-viral drug intervention is represented by diamond symbols, specifically denoting two events: (a) the first batch of Molnupiravir arriving in Taiwan and (b) the first batch of Paxlovid arriving in Taiwan. The transgression of the Rt rule (95% confidence intervals, CI), representing the effective reproduction number, is not specified in the given text. The data source for this information is the Taiwan Centers for Disease Control (CDC) (https://www.cdc.gov.tw/en/Disease/SubIndex/).

SARS-CoV-2 continues to undergo various mutations. According to the press release from Taiwan CDC on May 14, 2024, JN.1 was the most frequently detected variant in both domestic and imported cases in Taiwan, accounting for 88% and 64%, respectively. However, the KP.2 variant, a descendant of the JN.1 variant, comprised 5% of domestic and 12% of imported cases.⁵⁵ Meanwhile, based on the COVID Data Tracker from the United States CDC, KP.2 accounted for 28.2% of all circulating variants in the United States, surpassing JN.1, which stood at 15.7%.⁵⁶ Therefore, ongoing surveillance of SARS-CoV-2 variants remains essential. In Taiwan, the delayed replacement of dominant strains persists, with the FLiRT variants—descendants of JN.1, including KP.2 and KP.3—emerging as the predominant circulating strains after May 2024. These variants have been circulating in the United States since the spring of 2024.

From both the public health and individual perspectives, the most catastrophic result of the pandemic is mortality associated with infections. While the WHO reported 6.9 million documented COVID-19-associated deaths, statistical modeling estimated an additional death toll of 21.8 million due to COVID-19, with a 95% confidence interval ranging from 16.9 million to 30 million.^{57, 58} Throughout the course of the pandemic, Taiwan remained one of the countries that demonstrated the lowest rates of excess mortality, which is comparable to Singapore but higher than New Zealand (Excess rates per 100,000 people: Taiwan, 110; Singapore, 100; New Zealand: 7).⁵⁹ Compared to other countries, several factors may have contributed to the relatively lower excess death rate in Taiwan: broad vaccine coverage, widely used anti-viral agents, and delayed epidemic waves. First, COVID-19 vaccines have been proven to be highly effective in preventing disease-associated mortality, in which at least a 63% reduction in global death was averted by vaccination during the first year of vaccine rollout.⁶⁰ In Taiwan, the COVID-19 vaccine coverage rates in the population were as follows: 94% for the first dose, 89% for the second dose, and 76.7% for booster dose administration. The rate for the second additional dose also reached 47.6% for individuals aged 65 and above.⁶¹ Second, the introduction of oral anti-viral agents since February 2022 has improved accessibility to COVID-19 treatment, particularly for outpatients through telemedicine and digital prescription. By April 2023, 1,300,047 doses of oral nirmatelvir/ritonavir and molnupiravir were prescribed in Taiwan. Early intervention with oral anti-viral agents has been proven to shorten the clinical course and disease-associated hospitalization in influenza infection.^{62, 63} Similarly, the timely prescription of novel oral-anti-viral agents against SARS-CoV-2 has also demonstrated reduced risks of mortality and in-hospital disease progression in both clinical trials and real-world effectiveness studies.^64–66 Finally, the delayed epidemic waves in Taiwan has provided public health authorities with the opportunity to implement updated vaccine policies and ensure adequate storage of oral medications, especially oral anti-viral agents, thus contributing to effective response and preparedness.

Although Taiwan has opted to lift strict quarantine procedures, the spread and transmission of Omicron variants remain high, and we identified significant daily case numbers from May 2022 to January 2023 (Fig. 2). Monitoring the excess number of deaths at the national level is important during the exit stage. Furthermore, minimum measures for containing the spread of the disease, such as wearing masks in specific settings, need to be in place to prevent the health system from being overwhelmed by many mild COVID-19 cases. Breakthrough infections continue to occur, and the capacity of the healthcare system should be maintained to cope with the large number of mild cases. The continuous adjustment of restrictive measures based on the capacity of the local healthcare system is required. Given the scarcity of evidence on the impacts of various exit strategies, this rolling review can aid nations in identifying the most effective approaches.

Current updates and future perspective of COVID-19 vaccination

Since December 2020, several COVID-19 vaccines have been approved for emergency use. In Taiwan, the COVID-19 vaccination program began in March 2021 with the introduction of ChAdOx1 nCOV-19, followed by mRNA-1273 in June, MVC-COV1901 in August, BNT162b2 in October 2021, and NVX-CoV2373 in July 2022. Notably, the implementation of a mix-and-match vaccination strategy provided flexibility for individuals to receive different combinations of COVID-19 vaccines, resulting in more than 40 unique combinations being administered in Taiwan. ⁶⁷ Studies conducted during the emergence of the Omicron BA.2 and BA.5 variants revealed that mRNA vaccines induced higher immunogenicity than protein subunit and adenovirus vector vaccines.^68,69 The vaccine effectiveness against infection of a primary series adenovirus vector vaccine followed by a booster with an mRNA vaccine was comparable to that of a homologous mRNA vaccine booster.⁷⁰ A nationwide study in Taiwan among infection-naïve individuals found that the protein subunit vaccine’s effectiveness against hospitalization and death was comparable to that of mRNA vaccines, whether used as a primary series or as a booster. ⁷¹ Protein subunit vaccines could be an alternative platform due to their lower incidence of adverse events and comparable protection. Meta-analysis and nationwide studies revealed that a heterologous mRNA vaccine booster enhances immunogenicity and improves effectiveness against infection and severe outcomes compared to a homologous adenovirus vector vaccine and is not inferior to a homologous mRNA vaccine. ^72–75

COVID-19 vaccines have been developed with four primary objectives: providing protection against infection, preventing transmission, defending against severe disease, and mitigating the risk of long-term COVID-19. Initially, these vaccines exhibited remarkable efficacy against infections during the early pandemic period. However, over time, a decline in immunity has been observed due to the waning of antibodies and the emergence of highly immune-evasive VOCs.⁷⁰ The XBB sub-lineage, for instance, is approximately 63-fold more resistant to serum neutralization than BA.2, and 49-fold more resistant than BA.4/5.⁷⁶ Monoclonal antibodies that were effective against the original Omicron variant also exhibited limited activity against new sub-variants. The presence of these two distinct conditions has led to the establishment of a correlate of protection become increasingly complex. Nevertheless, vaccines that are better matched and more antigenically aligned with circulating variants provide a higher level of protection against severe disease.⁷⁷ Bivalent vaccines (wild-type/Omicron BA.4/5) induced higher neutralizing antibody titers against Omicron sub-lineages compared to monovalent vaccines (wild-type).⁷⁸ To better maintain vaccine-induced immunity, next-generation COVID-19 vaccines, including updated spike proteins from current circulating VOCs, are preferable. The bivalent booster immunization in immunocompromised patients exhibited similar effects to those healthy individuals.⁷⁹ However, neutralizing antibody titers against XBB.1 and XBB.1.5 declined to baseline levels within three months after bivalent boosting, while titers against other variants declined to a lesser extent.⁸⁰ After receiving bivalent booster vaccination, individuals with previous infections displayed higher levels of neutralizing antibodies compared to those without prior infection, but the relative increase in neutralization titers was higher in individuals without previous infections. In cases of the breakthrough infections caused by SARS-CoV-2 Omicron variants, better antibody responses were observed compared to vaccination alone.⁷⁶ Due to humoral immune imprinting, breakthrough infections with BA.2 and BA.5 variants reduced the diversity of neutralizing antibody binding sites and increased the proportion of non-neutralizing antibody clones.³⁴ The spikes of BQ and XBB sub-variants exhibited similar binding affinities to hACE2 as their predecessors. The recent growth advantage of novel sub-variants may be attributed to their ability to evade antibodies rather than their receptor-binding affinity.⁷⁶ Despite immune evasion by neutralizing antibodies, the XBB sub-lineages still respond to T cells, with over 80% of T cell epitopes being conserved across variants.⁸¹

Prior to the emergence of XBB sub-variants, the bivalent vaccine demonstrated superior protection against COVID-19 mortality compared with the monovalent vaccine, while there was no significant difference in vaccine effectiveness against infection between the bivalent and monovalent vaccines. In the United States, data revealed an infection rate ratio of 2.8 for unvaccinated individuals compared to those who received a bivalent booster and a ratio of 2.5 for those who received a monovalent booster; the mortality rate ratio was 14.1 for unvaccinated individuals compared to those who received a bivalent booster, and 5.4 for those who received a monovalent booster.⁸² Booster vaccination had a more pronounced effect in reducing mortality among older adults, with a mortality rate ratio of 23.7 for bivalent vaccine and 8.3 for monovalent vaccine. However, the efficacy of vaccines against mortality is less prominent among young people. The protection provided by booster vaccinations against mild diseases is short-lived. The crude vaccine effectiveness against mortality for monovalent booster was over 78% within 1 year, but it declined to 60% after 1 year.⁸² The crude vaccine effectiveness for bivalent booster against mortality declined from 94% to 88% during the BA.5- and XBB.1.5-predominant periods. The mortality rate ratios remained comparable between 2 weeks to 2 months and 3 to 6 months after bivalent booster vaccination in both the BQ.1/BQ.1.1- (11.4 and 11.0, respectively) and the XBB.1.5-predominant periods (8.4 and 7.3, respectively).⁸³ The bivalent vaccine offered significant protection against COVID-19-associated mortality in adults aged 65 and older, with no notable decline observed for up to 6 months post-vaccination.⁸³ The national database from Qatar revealed consistent observations indicating that the effectiveness against infection gradually diminishes over time following a booster vaccination and becomes insignificant after six months. The effectiveness in preventing severe, critical, and fatal cases was 75% when assessed after a year of follow-up. These results demonstrated a comparable level of effectiveness in clinically vulnerable individuals.⁸⁴

Hybrid immunity is the prevalent immunological status in a population. According to a nationwide study in Italy, the effectiveness of a second booster dose of the bivalent mRNA vaccine against severe COVID-19, relative to the first booster dose of an mRNA vaccine, was approximately 60% in individuals without a prior infection and in those who had a prior infection more than 6 months ago.⁸⁵ Individuals aged 60 years and older did not benefit from a second booster vaccination within 6 months post-infection. Among unvaccinated individuals with infection-induced immunity, better and longer-lasting protection against hospitalization was observed, compared to vaccination alone. Hybrid immunity among individuals with both prior infection and at least two vaccine doses demonstrated more than 90% effectiveness against hospitalization for at least 6–8 months, regardless of the type of prior infection or number of doses received.⁸⁶ Furthermore, a systematic review revealed that hybrid immunity and previous infection provided better and more sustained protection against severe disease or hospitalization than vaccination alone. The efficacy of a previous infection against severe disease was 74.6% at 12 months; however, its efficacy against reinfection decreased to 24.7% at 12 months. On the other hand, hybrid immunity against severe disease or hospitalization was over 95% at 12 months, while the effectiveness against reinfection decreased to 41.8% at 12 months.⁸⁷ However, the effectiveness of hybrid immunity in providing protection also declines as circulating variants continue to evolve. Data from Singapore showed that pre-Omicron variant infections with booster vaccination did not protect against infection by BA.4, BA.5, or XBB variants.³⁸ Previous BA.2 infection with booster vaccination offered greater protection against reinfection, but it was lower against XBB reinfection (51%) compared to reinfection with BA.4 or BA.5 (78%). Protection against XBB reinfection provided by a previous omicron variant infection with vaccination was lower and waned faster than protection against BA.4 or BA.5 reinfection. Hybrid immunity against novel sub-variants is not durable. However, the severity of the first infection or reinfection caused by XBB was lower than that caused by BA.4 or BA.5.³⁸

In a preclinical investigation, post-booster neutralizing antibodies induced by the monovalent Omicron XBB.1.5 vaccine were 5–8 times higher than those elicited by the bivalent vaccine, with a 3-fold higher response against the BA.2.86 lineage.⁸⁸ However, XBB.1.5 vaccines exhibited low neutralizing ability against BA.2.86 as part of the primary series. ⁸⁸ T cell responses were not significantly affected by the Omicron XBB.1.5 sub-lineage compared to earlier strains.⁸⁸

In real-world scenarios, the BNT162b2 Omicron XBB.1.5 vaccine substantially increased the neutralization responses against various SARS-CoV-2 lineages, including EG.5.1 and BA.2.86.⁸⁹ Following BNT162b2 Omicron XBB.1.5 booster vaccination, XBB.1.5 receptor-binding domain (RBD)-binding memory B cells (MBC) did not show significant changes but cross-reactive MBC exhibited a significant increase, suggesting persistent immune imprinting.⁸⁹ Neutralization titers against XBB.1.5, EG.5.1, HV.1, HK 3, JD.1.1, and JN.1 ranged from 13.3 to 27.6-fold. ⁹⁰ XBB infection and XBB.1.5 monovalent booster vaccination resulted in comparable antibody responses.⁹⁰ While XBB.1.5 monovalent vaccination after Omicron infection displayed the highest neutralization titers, the fold-increase was smaller. JN.1 appeared antigenically distinct, with titers against JN.1 being the lowest, 2.9-to-4.3-fold lower than those against XBB.1.5.⁹⁰ In May 2023, WHO has issued a recommendation that the new vaccine formulation for the year should target the prevailing XBB.1 descendent lineage, such as XBB.1.5. The original strain was excluded from the formulation because it was no longer in circulation in humans. The inclusion of the ancestral spike exacerbated immunological imprinting.⁹¹ Immunological imprinting was less severe for the XBB.1.5 monovalent vaccine than for the bivalent vaccine. XBB.1.5 monovalent booster vaccination increased antibody potency and breadth. As of April 2024, more than 94% of SARS-CoV-2 genetic sequences are derived from JN.1. XBB.1.5 and JN.1 are antigenically distinct variants. WHO recommend use of a monovalent JN.1 lineage as the antigen in formulation of COVID-19 vaccines this year.

Although children carry a lower risk of developing severe illness when acquiring COVID-19, vaccines are still a critical element in preventing COVID-19-associated morbidity, especially long-term COVID-19 syndrome, and multisystem inflammatory syndrome in children (MIS-C). The effectiveness of COVID-19 vaccines in preventing COVID-19 in children ranged from 40–70%.^92‒95 Considering the relatively low risk of severe outcomes in children coupled with a decline in the incidence of MIS-C, the necessity for additional booster vaccinations in children remains debatable. As we enter an era of high hybrid immunity, it is imperative to assess the added value of booster vaccinations for children and adolescents without underlying diseases.

The strategic objectives set forth by the WHO for booster vaccination encompass various crucial aspects of the medical field. These goals aim to minimize mortality, severe illness, and the overall burden of disease while also mitigating the impact on the healthcare system and reducing the negative consequences on socioeconomic activities. Additionally, they sought to diminish the risk of new emerging variants. High-risk individuals, including those aged 60 and above, individuals with moderate to severe immunocompromising conditions, individuals with comorbidities, and pregnant women, are among the primary targets for updated vaccination. These individuals require additional protection due to their vulnerability to COVID-19. Given the prevalence of hybrid immunity as a prevailing immunological state, it is noteworthy that it has exhibited an effectiveness exceeding 90% in mitigating severe disease or hospitalization over a 12-month period. Based on this observation, an annual booster vaccination strategy is considered appropriate for individuals at heightened risk of contracting COVID-19. WHO recommends co-administration of COVID-19 vaccines with seasonal influenza vaccines or other respiratory vaccines, whenever epidemiologically justified. Given the continuous evolution of these variants, it is imperative to develop next-generation vaccines that specifically target the highly conserved neutralizing epitopes. Such vaccines should aim to minimize viral mutations and employ vaccine platforms that have demonstrated the ability to offer durable, localized protection in the nasal mucosa, effectively hindering viral transmission.⁹⁶ These long-term strategies are essential for combating the ongoing challenges posed by the COVID-19 pandemic.

Conclusion

The integration of public health and biomedical science played a significant role in ending the emergency phase of the pandemic. In the post-pandemic era, more collaborative measures are still necessary to reduce SARS-CoV-2 transmission. Timely surveillance of circulating variants and sub-variants cannot be overemphasized. Ongoing studies on the effectiveness of vaccines against severe COVID-19, considering immune evasion as the primary survival advantage that triggers viral evolution. Vaccination strategies for high-risk populations and the development of next-generation vaccines to reduce the transmission of SARS-CoV-2 should be discussed based on updated surveillance data.