From March 1, 2023, all the Coronavirus disease 2019 (COVID-19) restriction measures have been lifted in Hong Kong including the mask mandate, getting the society back to normal.¹ However, there is a rebound of local COVID-19 cases caused by predominantly XBB, an Omicron sub-variant, and its descendant lineages.² In fact, the Centre for Health Protection (CHP) of the Department of Health reported an upward trend of severe COVID-19 diseases over the past 3 months, with 236 cases in week 21 of 2023 (i.e., May 18-24, 2023), representing an increase from 195 cases 2 weeks before.² Besides, the community begins to face enormous challenges from long COVID among the recovered patients.³ Undoubtedly, the threat of COVID-19 remains and the preventive measures, particularly COVID-19 vaccination, are still warranted to confer protection to the general public, especially those who are at the risk of severe diseases. In an interview with Omnihealth Practice, Professor Stephen J. Thomas from SUNY Upstate Medical University discussed the current COVID-19 situation around the world and emphasized the need for the public to be vaccinated with the variant-adapted BNT162b2 bivalent vaccine.

The ongoing health risks of Omicron XBB sub-lineages

Omicron XBB is a recombinant sub-lineage, with the offspring XBB.1 resulting from the recombination of BA.2 and BA.2.75.⁴ The XBB family obtains a wide range of additional mutations on the spike (S) protein,  rendering them a greater growth advantage and immune escape properties (i.e., highly transmissible and the infected people are prone to have vaccine-breakthrough infection or reinfection).^4,5 First identified in India in August 2022, these new subvariants have rapidly spread to other countries, including the United States (US).⁴ As of May 2023, they have already accounted for >95% of COVID-19 infection and become the predominant variants in the US.⁶ Likewise, the latest data in Hong Kong showed that XBB and its descendant lineages comprised about 95.8% of all the characterized specimens in late May 2023.²

In fact, concerns have been heightened in the scientific community over the continuous evolution of the virus. Antigenic changes hat result from mutations may lead to the emergence of new sub-lineages, compromising the efficacy of the existing vaccines and therapeutics against severe COVID-19 diseases.⁴ The health of vulnerable people, especially the elderly and immunocompromised, is therefore at stake. Prof. Thomas emphasized that COVID-19 infections can lead to significant distress and potentially long-lasting health impact on the general population, it is crucial for even healthy individuals (those without risk factors) to stay alert and maintain vigilance.

Long COVID poses long-term health challenges

Long COVID, also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC) infection or post-COVID syndrome, is a constellation of signs and symptoms involving multiple organs that could persist for weeks or months after the initial COVID-19 infection.³ It has emerged as a public health concern after studies estimating that 54%-80% of COVID-19 survivors experienced ≥1 long-COVID-19 symptoms.³ Data have shown that patients with a history of severe COVID-19 disease, a greater degree of multi-morbidities, <2 doses of COVID-19 vaccines prior to infection, or at an advanced age of ≥65 years were found to have a greater risk of long COVID.³ A large population-based long COVID survey, conducted by the Chinese University of Hong Kong (CUHK), revealed that up to 70% of patients previously infected with Omicron suffered from lingering COVID symptoms with a median duration of 5 months.⁷ The health consequences of long COVID are found to be substantial.⁸

Since SARS-CoV-2 invades the target cell by binding to angiotensin-converting enzyme 2 (ACE2) receptors, which are widely expressed in the reproductive organs such as testicles, ovaries and uterus, the CUHK survey showed that 12% of long COVID patients (of which 80% were women) had reproductive problems, including menstrual irregularity, sexual dysfunction or increased sensitivity in the groin area.⁷ Long COVID patients were also reported to have a two-fold increased risk of reduced libido and ejaculation difficulty.⁷

Additionally, a retrospective, multi-database cohort study in Hong Kong and the United Kingdom identified previous COVID-19 infection as a risk factor for diseases involving multiple organ systems during the post-acute phase of infection.³ For instance, COVID-19 patients had an 82% significantly greater risk for heart failure (HF), 74% for deep vein thrombosis (DVT), 61% for chronic pulmonary disease, 65% for anxiety disorder, 76% for end-stage renal disease (ESRD), and 42% pancreatitis (table 1).³ They also had a much higher risk for cardiovascular events (HR=2.86; 95% CI: 1.25-6.51) and all-cause mortality (HR=4.16; 95% CI: 2.11-8.21).³

Bivalent BNT162b2 vaccine: Boosted immunity to Omicron variants, including XBB

As the SARS-CoV-2 continues to evolve, the effectiveness of the ancestral strain vaccines is continually being challenged.⁹ Variant-adapted vaccines are, therefore, urgently needed to counteract the enhanced immune escape of the predominant variants. In August 2022, the US Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA) for the bivalent BNT162b2 vaccine which combines the ancestral spike messenger ribonucleic acid (mRNA) with Omicron BA.4-5 spike mRNA for active immunization to prevent COVID-19 and as a single booster among individuals aged ≥12 years.¹⁰

The effectiveness of bivalent vaccines against Omicron variants (i.e., BA.4.6, BA.5, BQ.1, and BQ.1.1) was demonstrated in a large cohort study, in which a total of 292,659 participants received monovalent boosters from May to August 2022, and 1,070,136 people received the bivalent boosters from September to December 2022 in the US.¹¹ Results showed that the BNT162b2 bivalent vaccine provided additional protection against Omicron infection and achieved a higher vaccine effectiveness (VE) [i.e., (1 – HR) x 100%] against hospitalization or death of 60.4% (95% CI: 42.1-73.0) when compared with the monovalent BNT162b2 vaccine (VE: 24.5%; 95% CI: -10.7 to 48.5), with a significant difference in VE of 35.9% (95% CI: 3.7-75.5).¹¹

Nonetheless, since bivalent BNT162b2 contains mRNA that encodes the S-gene from the ancestral strain and Omicron BA.4/BA.5 while XBB and XBB.1.5 are descendants of the Omicron BA.2 sub-lineage, there were concerns about the potential reduction in the VE of bivalent BNT162b2 against these predominant subvariants.¹² Yet, a recent immunogenicity study has indicated that the bivalent vaccine elicited several times higher neutralizing titers when compared with the ancestral strain vaccine against the BA.2.75.2, BQ.1.1 and XBB.1 sub-lineages (figure 1).¹³ The findings suggested that the bivalent vaccine was much more immunogenic, supporting its use in real-world practice.

The real-world effectiveness of bivalent BNT162b2 as a single booster against XBB/XBB.1.5 infection has been demonstrated in a US surveillance program. The study showed the bivalent vaccine was equally effective in preventing symptomatic infections caused by Omicron BA.5 and XBB/XBB.1.5 among immunocompetent adults who had previously received 2-4 ancestral strain BNT162b2 doses.¹² The VE of a bivalent booster among persons aged 18-49 years was 48% against symptomatic XBB/XBB.1.5 infection and was similar to that against symptomatic BA.5 infection (52%).¹² The encouraging results suggested that the bivalent vaccine continues to provide additional protection to people during the XBB-predominant period.

Risk of long COVID reduced with effective COVID-19 vaccination

In Hong Kong, the bivalent BNT162b2 vaccine has been approved for active immunization as a booster dose to prevent COVID-19 in individuals aged ≥12 years.¹⁴ Since October 2022, the Hong Kong Joint Scientific Committees joined by the Chief Executive’s expert advisory panel (JSC-EAP) recommends the use of bivalent BNT162b2 vaccine in individuals who have received ≥3 doses of ancestral strain vaccine as the subsequent dose.¹⁵ According to the latest JSC-EAP’s recommendations, persons aged ≥50 years including those living in residential care homes, persons aged 18-49 years with underlying comorbidities, persons with immunocompromising conditions aged ≥6 months, pregnant women and healthcare workers, are regarded as the high-risk priority groups.¹⁵ These people are recommended to receive an additional bivalent booster (or boosters) ≥6 months after the last dose or COVID-19 infection (whichever is later).¹⁵ “In fact, apart from those who are at the risk of severe COVID-19 disease, hospitalization or death, people who do not have the risk factors but are concerned about the consequence of COVID-19 infection (e.g., long COVID) may also want to receive a bivalent booster,” suggested Prof. Thomas.

As mentioned above, long COVID is found to have a long-term impact on the health of COVID-19 survivors. An observational cohort study (n=2,560) conducted between March 2020 and April 2022 in Italy showed that COVID-19 vaccination was associated with a lower prevalence of long COVID.¹⁶ Specifically, people who had received 2 doses of COVID-19 vaccine were 75% (OR=0.25; 95% CI: 0.07-0.87; p=0.03) less likely to suffer from long COVID; while the likelihood of long COVID was 84% (OR=0.16; 95% CI: 0.03-0.84; p=0.03) lower for those having received a booster (i.e., 3 doses).¹⁶ According to Prof. Thomas, the potential of COVID-19 vaccination to prevent or reduce the effects of long COVID may be a reason to consider vaccinating even those who are not in high risk groups.  

In April 2023, the US FDA authorized bivalent BNT162b2 vaccine to be used for all recommended doses administered to individuals aged ≥6 months.¹⁷ Accordingly, the CDC recommends that everyone aged ≥6 years and older should receive the bivalent mRNA COVID-19 vaccine, regardless of whether they have previously completed their monovalent primary series.¹⁷ In other words, bivalent BNT162b2 vaccine can be used in the primary vaccination schedule and as subsequent booster doses. It is believed that this new approach may help simplify the dosing schedule, decrease administration errors, and encourage future vaccination. 

What is the future COVID-19 vaccine development?

Although the existing vaccines have achieved a profoundly positive effect in reducing hospitalization and death during the COVID-19 pandemic, the necessity of repeated booster doses to sustain the protection and the emergence of “vaccine fatigue” present a public dilemma.^18,19 Besides, since a new dominant SARS-CoV-2 variant may emerge every 3-4 months, the current approach would be inadequate in the long run.¹⁸ A long-term strategy with a next-generation vaccine that can offer longer protection (i.e., at least 1 year) with greater scope (i.e., applicable to a wide range of potential variants that might emerge) is therefore desired.¹⁸

Currently, investigation of novel approaches for the future COVID-19 development is underway, including methods targeting S protein viral sequences that are immutable, immunogenic and accessible to neutralizing antibodies.¹⁸ Other targets include portions of the membrane, envelope, or nucleocapsid proteins.¹⁸ In addition, some researchers attempt to use nanoparticles to target conserved or occluded epitopes (i.e., structurally hidden).¹⁸ Efforts are also being made to develop vaccines utilizing T-cell receptor constructs designed to specifically recognize the RNA-dependent RNA polymerase of SARS-CoV-2.¹⁸

Conclusion

In summary, Prof. Thomas cautioned that even though some strains of SARS-CoV-2 might cause less severe disease, the COVID-19 era is far from over. He also stressed that Omicron sub-variants continue to pose a threat, causing severe illness or even death among high-risk individuals, and can lead to serious illness in the general population as well. Long COVID is another concern, and it's essential for everyone to stay vigilant and use the available preventative measures, particularly the BNT162b2 bivalent vaccine. Ultimately, effective COVID-19 vaccination remains the most critical and reliable method to protect the public against the virus in the long run.