The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has deviated a lot from its ancestral strain via antigenic drift.¹ As such, the immunogenicity offered by earlier vaccines may be diminished against newer variants.² The XBB strain and its sublineages are the latest variants of concern (VOC) and are the most prevalent strains of Coronavirus disease 2019 (COVID-19) as of October 2023.³ The World Health Organization Strategic Advisory Group of Experts on Immunization  (WHO-SAGE) has issued a report in November of 2023 advising the use of a vaccine that matches the circulating variant.⁴ In a recent symposium organized by the Hong Kong Society of Infectious Disease on December 4^th  2023, Professor Hung, Fan-Ngai Ivan shared the latest perspectives on the use of the monovalent XBB messenger ribonucleic acid (mRNA) vaccine (XBB.1.5 MV) which has shown promising immunogenicity data derived from both circulating and emerging variants.^5,6 The Hong Kong Joint Scientific Committee (JSC) also echoes this recommendation, urging vulnerable populations to receive their booster doses before the winter months begin.⁷

 

The dominant XBB variant represents significant antigenic drift

SARS-CoV-2 has continued to evolve rapidly with the Omicron XBB variants quickly overtaking BA.4/5 as the dominant strain as we step into the fifth year of the COVID-19 pandemic in late 2023. This trend is seen in data across China and is supported by epidemiological data locally in Hong Kong.^3,8 Reports from the Chinese Center for Disease Control and Prevention (China CDC) have revealed that as of October 2023, all circulating strains are among the Omicron XBB series (e.g., XBB.1.9, XBB.1.22, and XBB.1.16), and that earlier BA strains have faded into obscurity (figure 1).³ The statistics in Hong Kong in October were aligned with the global trend as well as up to 99.1% of cases of severe disease or death from COVID-19 were attributed to Omicron XBB strains and their sublineages.⁸

Prof. Hung presented that the dominating sublineages of XBB1.5 and XBB.1.16 are the most antigenically distant variants to date from both the Omicron predecessor and its ancestral strain (figure 2) due to the extensive hybrid immunity built up over the years from both infections and vaccinations.¹ The extent of this antigenic drift of the XBB strain is comparable to the antigenic leap made by the initial Omicron variant, allowing these strains to escape hybrid immunity and exhibit far greater antigenic resistance, possibly fueling another surge of COVID-19 infections.¹ Thus, it is important to develop vaccines that protect broadly and anticipate the antigenic trajectory of SARS-CoV-2.¹

Selecting a vaccine with the appropriate target antigen

In response to the antigenic drift of SARS-CoV-2, Prof. Hung emphasized that the vaccines must evolve alongside the virus to maintain their efficacy against breakthrough infections.^1,9 Studies conducted in earlier vaccine formulations like the inactivated vaccines have shown that cross-neutralizing antibodies (nAbs) against the newer XBB lineages has decreased  despite having hybrid immunity.⁹ A real-world study conducted in China investigated the antigenic resistance of the newly emerging XBB variants among patients who had previously received multiple doses of inactivated vaccines, and had breakthrough infections with the ancestral, Delta, BA.1, or Omicron BA.5 strains.⁹ Although hybrid immunity did increase the levels of plasma nAbs, the neutralization activity was remarkably impaired to a nearly undetectable level against the XBB, XBB.1, or XBB.1.5 strains.⁹ These results reveal the need for new COVID-19 vaccines due to the evasion capabilities of emerging variants.⁹

The same concept can be applied to booster vaccinations where an updated formulation that matches the circulating variant is equally important.² In a study comparing the neutralizing response elicited by bivalent boosters against the BNT162b2 wild type monovalent booster, it was found that bivalent boosters containing mRNA against both the ancestral strain and the BA.4/5 strains conferred better immunity across the board against the ancestral strain, the BA.4/5 strain, and the XBB strain over the mRNA vaccine regardless of prior infection.² Against the ancestral strain virus, both the bivalent booster and the ancestral booster conferred similar results in terms of geometric mean titer (GMT) at 1 month post-booster.² The bivalent booster had a higher GMT of 2,237 compared with the monovalent vaccine with a GMT of 1,325.² However, the immunity of both boosters diminished over time as the newer strains emerged starting with the BA.4/5 strain virus where the bivalent vaccine elicited higher immunogenicity against the antigenically aligned variants, demonstrating a GMT of 518 compared with 89 with the monovalent booster.² Both boosters achieved relatively low GMT against the latest XBB.1 strain with a GMT of 55 and 17 for the bivalent and monovalent booster, respectively.² This study shows that regardless of the hybrid immunity from prior infections and vaccinations, better immunity may be achieved with a vaccine that matches with the specific SARS-CoV-2 variant in circulation.²

Prof. Hung said that “We definitely need a well-matched vaccine with the XBB variant.” A statement released by the WHO-SAGE in November 2023 similarly acknowledged the evolving epidemiology of SARS-CoV-2.¹⁰ Previously, the WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) stated that after 4 years of the pandemic, seroprevalence is high either because of infections or vaccination in the global population but the immunological profile against the virus remains heterogenous with limited in-vitro evidence of immune imprinting.¹⁰ They recognized that there is continuous and substantial antigenic evolution of the virus with an evolutionary trajectory that continues to diverge from the index virus and that there are substantially lower levels of nAb against XBB lineages than nAbs against BA.4/5 lineages after receiving the bivalent vaccines.¹⁰ Furthermore, despite limited vaccine effectiveness data, preclinical data have demonstrated that XBB.1 vaccines may elicit high nAbs to circulating variants.¹⁰

The WHO, along with the US Food and Drug Administration (FDA) and the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) have decreed that the monovalent XBB.1 descendent lineage (e.g., XBB.1.5 or XBB.1.16) should be the vaccine antigen of choice in the coming autumn and winter season of 2023-2024.^10,11,12 The WHO further advise moving away from the inclusion of the index virus in upcoming vaccine formulations as the ancestral strain no longer circulates in humans leading to the index virus antigen eliciting almost undetectable levels of nAbs against currently circulating variants.¹⁰ In fact, the inclusion of earlier antigens including the ancestral strain and bivalent vaccines may reduce the concentration of the new target antigens and cause immune imprinting which possibly diminishes the magnitude of the humoral or immune response against circulating variants.¹⁰ The Hong Kong JSC also released similar recommendations for COVID-19 vaccination in 2023-2024.⁷ In view of the latest immunogenicity and safety data, the new monovalent XBB.1.5 mRNA vaccine was considered the preferred vaccine of choice.⁷

Real-world evidence of BNT162b2 XBB.1.5 vaccine against Pan-XBB and BA.2.86 stains

Prof. Hung claimed that there were very encouraging real-world data on both the humoral and immune responses so far with the monovalent mRNA vaccine, BNT162b2 XBB.1.5, which was developed to target the XBB.1.5 spike protein.⁵ The effectiveness of the BNT162b2 XBB.1.5 against pan-XBB variants was investigated in a real-world setting.⁵ The majority (66%) of study participants (n=65) had previously received ≥4 vaccinations with 29% (n=19) having had a bivalent vaccine and 82% (n=53) having reported previous SARS-CoV-2 infections.⁵ At 8-10 days post-vaccination, potent neutralizing responses were recorded against both the previous and contemporary SARS-CoV-2 lineages. Increased response was reported across the board except for the B.1 pseudovirus particle (pp) which had similarly high response.⁵ The neutralization of all other tested pps showed a significant median increase in order of magnitude from BA.2.86 (17-fold), to XBB.1.16 (32-fold), EG.5.1 (34-fold), XBB.1.5 (44-fold), and XBB.2.3 (48-fold).⁵ The humoral response pre- and post-vaccination stratified by pp type is presented here (figure 3).⁵

Real-world utility against emerging SARS-CoV-2 strains (HV.1, HK.3, JD.1.1 and JN.1)

A robust boost in neutralizing antibody response was also noted against emerging SARS-CoV-2 strains including the HV.1, HK.3, JD.1.1, and JN.1 strains in the real-world setting after the administration of updated monovalent mRNA vaccines against XBB strains.⁶ According to a study conducted in 2023 in the United States (US), XBB.1.5 monovalent vaccines (XBB.1.5 MV) have maintained their efficacy in the latest circulating strains of SARS-CoV-2.⁶ Among previously uninfected individuals (n=8), XBB.1.5 MV has significantly increased the 50% inhibitory dilution titer (ID₅₀) post-administration by 32.0-fold against XBB.1.5 strains and by 24.1-fold against EG.5.1 strains. Additionally, the ID₅₀ against emergent strains including HV.1, HK.3, JD.1.1, and JN.1 strains after receiving XBB.1.5 MV was increased by 13.3- to 27.4-fold.⁶ The population with hybrid immunity by the XBB.1.5 MV vaccine and prior Omicron infections (n=25) had higher neutralization titers both before and after XBB.1.5 MV compared with previously uninfected individuals, but had a smaller relative increase post-XBB.1.5 MV vaccination.⁶ In this population, the increase in neutralization activity was much higher in newer omicron variants like HV.1 (9.3-fold), HK.3 (9.4-fold), JN.1 (9.5-fold), JD.1.1(10.6-fold) compared with the BA.5 variant (3.9-fold).⁶ This study offers an optimistic outlook for the use of XBB.1.5 MV against the upcoming variants of interest as more data accumulate over time.⁶

Buckling up for the winter surge and seasonal morbidities

In view of the robust clinical data of XBB.1.5 MV vaccinations, the latest WHO-SAGE guidelines of November 2023 have updated their views on the importance of vaccination with an antigenically-matched vaccine specifically for the coming season.⁴ Although clinical symptoms of the current iteration of COVID-19 have become relatively less severe, with the China CDC having reported 0 deaths from respiratory failure caused by COVID-19 infection alone, SARS-CoV-2 still poses a significant threat to vulnerable populations with underlying comorbidities combined with COVID-19, leading to 24 deaths reported over the same period.³ This is particularly true for the autumn and winter months as SARS-CoV-2 has a seasonality of disease activity akin to the influenza A virus (flu) or respiratory syncytial virus (RSV) infections.¹³ Prof. Hung voiced his concerns “of an expected rise in infection rates of COVID-19 followed by the flu overlapping with the RSV in the upcoming winter months.” The risk of hospitalization from COVID-19 spikes every year during these months, disproportionately affecting the elderly population (figure 4), presenting a debilitating and deadly threat.¹⁴ Noting the consequences for these populations, Prof. Hung cautioned that “we should be focusing on the high-risk individuals, especially those in elderly homes or are immunocompromised. When they come down with the very infectious XBB strain, they could come down with a more severe disease.”

Guideline recommendations on vulnerable populations

The WHO has recommended different schedules of vaccination based on the risk of different demographic groups.¹⁵ The high-priority group included older adults, younger adults with significant comorbidities (e.g., diabetes and heart disease) or severe obesity, people with serious immunocompromising conditions (e.g., transplant recipients, patients on immunosuppressive treatment; cancer patients), pregnant persons, as well as frontline health workers.¹⁴ They are recommended to receive additional booster doses 6 or 12 months after the last dose of the primary series, and the first booster dose, but the schedule is subject to factors such as age and immunocompromising conditions.¹⁴ In the medium priority group, such as healthy younger adults under the age of 60 and children and adolescents with severe obesity or comorbidities that put them at higher risk of severe COVID-19 infection, additional booster doses outside of the primary series and first booster dose are not routinely recommended.¹⁴

The Hong Kong JSC also released similar recommendations for COVID-19 vaccination in 2023-2024 aligning with the WHO presented in Table 1.⁷ People within the high-risk groups should receive their booster doses in accordance with the latest recommendations. Furthermore, booster doses should be administered before a possible COVID-19 winter surge as the optimal timing.⁷

Conclusion

The antigenic profile of SARS-CoV-2 has drifted far from its ancestral strain and vaccination antigens should match the drift to offer better protection against COVID-19.¹⁰ The WHO and Hong Kong JSC have recommended the XBB.1.5 MV as the vaccination of choice with promising immunogenicity data in the circulating and emerging variants with WHO emphasizing that older formulations based on the ancestral strain should be avoided as they are no longer circulating in human populations.^10,7 Prof. Hung concluded the symposium with a reminder that as the winter months approach, severe cases of COVID-19 may spike yet again. Booster vaccinations with the right vaccine formulation may be the key to reducing infections among vulnerable populations.⁷