Introduction
Recent surges in COVID-19 cases around the world, coupled with the emergence of BA.2.86 and its sub-variants such as JN.1, have highlighted that while the SARS-CoV-2 pandemic continues to evolve, it is certainly not over.[1] However, pandemic fatigue, misinformation, conflicting information in the media, and a lack of perceived risk from COVID-19 all pose significant obstacles to maintaining vaccination coverage around the world.[2] As in other regions, recommendations are in place in Singapore and other Southeast Asian countries to offer COVID-19 booster vaccinations to high-risk groups, such as people over the age of 60, those who are medically vulnerable, and aged care facility residents.[3] The current vaccine recommendations include:
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everyone aged 5 years and older are recommended to have one dose of an updated COVID-19 vaccine to protect against serious illness from COVID-19[4]
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it is encouraged that children aged 6 months and above receive updated doses, in particular household members of medically vulnerable individuals.[3] For this age group, multiple doses of COVID-19 vaccines may be required to be up to date, including at least 1 dose of an updated COVID-19 vaccine.[4]
Access to the latest vaccine should be supported by proactive measures by physicians and health authorities to ensure patients are aware of the risks of SARS-CoV-2 infection, particularly the longer-term consequences, and understand the benefits of booster vaccinations.
Tables 1 and 2 detail the vaccinations, antivirals, and monoclonals referenced throughout the discussion. Prescribers should refer to the individual summaries of product characteristics and local guidelines for further information and recommendations regarding the use of pharmacological therapies.
Table 1: The approved vaccines referenced in the discussion
Table 2: Antiviral and monoclonal therapies referenced in the discussion
The burden of disease and risks associated with COVID-19
Changing prevalence of COVID-19 and emergence of SARS-CoV-2 variants 2020–2023
How has COVID-19 prevalence changed over time and which variants have been important?
Pattarin Pirompanich (PP): Thailand's strict public health policy initially controlled COVID-19 effectively, but then hospitals were overwhelmed during the Delta wave in 2021 and again during the first Omicron wave at the beginning of 2022.[5]
Barnaby Young (BY): In Singapore, control measures were effective during 2020 and much of 2021. Widespread community transmission was first documented with the emergence of the Delta variant and continued during successive waves of Omicron, that have occurred from early 2022 until now.[6]
Tobias Welte (TW): The original wave of SARS-CoV-2 infection peaked in Europe in the late spring of 2020 and was followed by Alpha, Beta and Delta waves 2020–2021, then Omicron and its descendent variants from late 2021. Community transmission occurred during each wave, despite unprecedented public health measures. Morbidity and mortality rates due to acute infection were highest in 2020, then reduced with the introduction of vaccination at the end of 2020, and then fell further from early 2022 as Omicron became dominant.[7]
What is the current prevalence of COVID-19 (October 2023)?
BY: Accurate patient-level data is not available as widespread community testing for COVID-19 and reporting of results is no longer performed in Singapore. Hospitals use PCR diagnostic tests for patients with respiratory symptoms to detect influenza, SARS-CoV-2, and respiratory syncytial virus (RSV) infection.
PP: We have the same situation in Thailand. Earlier this year, routine screening was conducted for all patients admitted to hospitals, but this practice has been discontinued. Currently, only patients presenting with respiratory symptoms are tested.
TW: We have no comprehensive European data on the infection rate as community testing is no longer routine, so many cases remain undiagnosed.
What are the demographics of SARS-CoV-2 infection in your region?
TW: The highest rate of infection in Europe occurs in the elderly, particularly in people over 75. This group is still vulnerable because their immune response to vaccination declines rapidly, and they are more likely to have comorbidities. One of our hotspots for outbreaks is nursing homes.[8]
PP: Data from a cross-sectional study shows that the highest infection rate occurred in Thailand in children under five.[9] The rate in the elderly is lower, possibly due to cultural differences compared to Europe. Here, the elderly are cared for in their family home, not in nursing homes.
Prevalence of severe disease due to SARS-CoV-2 infection
Which factors affect the progression of SARS-CoV-2 infection to severe disease?
TW: The consequences of SARS-CoV-2 infection depend on the variant and on the health status and vaccination status of the person infected:
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The acute effects of COVID-19 infection (morbidity and mortality due to respiratory infection) are lower with Omicron and its descendant variants compared to earlier variants.[10]
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Children and adults (up to 60 years) with no comorbidities have less severe disease; symptoms of SARS-CoV-2 infection are mild, or the individual is asymptomatic.[11]
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Vaccination does not protect against infection, particularly with Omicron, but does protect against progression to severe illness and hospitalisation.[10]
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Older people are more at risk of severe disease due to SARS-CoV-2 infection; vaccination reduces that risk but immunity wanes more quickly in the elderly. Booster doses are required to rescue antibody levels.[12]
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Elevated mortality rates due to acute COVID-19 infection are observed in people of all ages in high-risk groups such as transplant recipients, patients with haematological malignancies, and those undergoing B-cell depletion therapy for autoimmune diseases.[13] In my centre, the largest transplant facility in Europe for both kidney and lung transplants, we continue to see a mortality rate of around 5%, even with the milder Omicron variant.
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Some people experience long-term effects including cardiovascular, metabolic and other non-respiratory complications and, of course, 'long covid', but the risk factors are not well understood. Studies have shown that SARS-CoV-2 infection doubles the rate of cardiovascular complications in the three months following acute infection.[14]
Has the incidence of severe disease associated with SARS-CoV-2 infection changed over time?
BY: Delta caused approximately 150,000 cases in Singapore with significant hospitalisations and mortality. The subsequent large waves of Omicron due to the variants BA1/BA2, XBB and most recently EG.5.1 and JN.1 have also led to high case numbers but fewer cases of severe illness. As a result, pressure on hospital beds and Intensive Care Unit (ICU) admissions remains low.[15]
PP: In Thailand, the XBB.1.5 wave was followed by XBB.1.16 and EG.5.1 currently dominates.[16] Hospitals and ICUs in Thailand are relatively stable in terms of COVID-19 cases; the primary concern has shifted towards managing the ongoing influenza outbreak.
TW: In Europe, we have a similar situation, the EG.5.1 variant is present but without a notable impact on hospitals or ICUs. The Omicron variant tends to cause milder disease, but the population has robust immunity from both vaccination and natural infection; around 98% of the population have high titres of anti-SARS-CoV-2 antibody.[17]
What is the impact of COVID-19 vaccination antiviral, and monoclonal therapies on acute and long-term complications?
COVID-19 vaccination
The COVID-19 vaccines discussed are listed in Table 1.
Does availability of COVID-19 vaccines vary across different regions?
TW: In general, availability of specific COVID-19 vaccines depends on political and economic factors; the choice of vaccines within a given country is determined by recommendations from local vaccine advisory committees, rather than by formal guidelines.
The AZ vaccine was the first to be used in Europe, but mRNA vaccines now constitute approximately 99.5% of all doses administered. Germany primarily offers the Pfizer vaccine; the Moderna vaccine is available, but at a cost. Novavax and other vaccines form a very small proportion of the vaccination portfolio.[18]
PP: The inactivated Sinovac and Sinopharm vaccines became available in Thailand first, followed by the AZ vaccine. Later in 2021, the Pfizer mRNA vaccine was approved and Novavax became available mid 2022.[19] Heterologous COVID-19 vaccination is typical in Thailand.
TW: Data shows that heterologous vaccination has a slightly enhanced efficacy compared to a homologous regimen.[19,20]
BY: In Singapore, the Pfizer and Moderna vaccines have been the primary options.[21] Healthcare workers were among the first to receive the Pfizer vaccine, in late December 2020, followed by the introduction of Moderna a few months later. Initially, individuals received two doses, with a third booster dose recommended from September 2021. This booster was integrated into existing vaccine-differentiated measures that impacted employment opportunities, access to public buildings, and social interactions.
The inactivated vaccines, Sinovac and Sinopharm, were administered to a minority, specifically to individuals with allergies or opposition to mRNA vaccines. Novavax became available in May 2022.
What is rate of uptake of COVID-19 vaccines in your region?
BY: To date, approximately 95% of adults in Singapore have had two vaccination doses, 80% have had at least one booster.[21] Most children have received two doses of mRNA vaccine, and vaccination is recommended for children from the age of six months, though uptake is lower among the under-fives.[21]
TW: In Germany, approximately 70% of the population has received three doses, and a significant number have had four or five.[22] Booster uptake has declined due to vaccine fatigue, decreased awareness of its importance, and social media misinformation. Europe currently does not advocate boosters for children.
PP: More than 60% of the Thai population have had three doses of vaccine. Seroprevalence is around 90%, even in people who have not had history of SARS-CoV-2 infection.[8] Younger people are less likely to accept a booster vaccination, possibly due to the increased risk serious adverse effects in the 12–17 age group. Data from retrospective cohort studies shows that this age group has 25 times the risk of these serious side effects compared to the over 65s.[23]
How immunogenic are the various vaccines?
BY: Data indicate that the inactivated Sinovac and Sinopharm vaccines elicit weaker primary antibody responses compared to mRNA vaccines. However, focusing solely on antibodies to the spike protein and the receptor binding domain (RBD) overlooks the data showing that T-cell immunity appears to be quantitatively comparable but broader with inactivated vaccines.[24]
PP: Inactivated vaccines were used initially in Thailand and the data shows that these were a good primer; subsequent boosting with an mRNA vaccine produced a large spike in antibody levels.[25]
BY: We also made that observation in Singapore, but giving the mRNA vaccine before an inactivated vaccine booster was nowhere near as effective. However, interpreting data is complicated because people had also experienced SARS-CoV-2 infection.[26]
TW: It would be interesting to examine the differences in B- and T-cell mediated immunity in people from SE Asia who have received inactivated vaccines then mRNA vaccines compared to people in Europe who have received AZ followed by mRNA vaccines. In my opinion, loss of immunogenicity occurs more quickly with mRNA vaccines compared to classical vaccine technology.
How effective is vaccination at preventing infection/severe illness?
BY: Although the original clinical trials on the primary vaccination series showed protection against infection exceeding 95%,[27] real-world data shows this is not achieved with the emergence of Omicron and its descendant variants.[28] The duration of protection against infection is relatively short and effectiveness against transmission of SARS-CoV-2 is poor; despite a 95% vaccination rate, 80–90% of the population in Singapore has been infected.[21]
In contrast, vaccination does provide protection against severe disease, making hospital admission for acute infection less likely.[29,30] This protection is long-lasting and is further boosted by repeat vaccination.[12]
TW: Reduced protection against Omicron and its descendants probably stems from the ability of the virus to evade immunity rather than diminished vaccine efficacy.
Is vaccination effective at preventing longer term complications of SARS COV-2 infection?
TW: Current data on the protection offered by COVID-19 vaccination against long-term severe outcomes is limited. SARS-CoV-2 infection, like influenza infection, increases the risk of major cardiovascular events—myocardial infarction, stroke, left heart failure, and atrial fibrillation post-infection.[14] While influenza vaccination has been shown to reduce the risk of these events by 34%,[31] equivalent data for COVID-19 vaccination are not yet available.
The second concern is long covid, an as-yet undefined condition, which is therefore challenging to investigate. Some data suggests that vaccination may help prevent it, but the evidence is not particularly robust.[32] Also, the Omicron variant has been linked anecdotally to a lower incidence of long covid.
What is the response to vaccination in people from high-risk groups?
TW: Many patients in Europe are now vaccinated, most with multiple boosters, but a third of the high-risk patients I treat in Germany do not show any measurable antibody response to vaccination. The vaccines can also elicit T-cell immunity, but potency varies between individual patents. Our unpublished data shows that strong T cell immunity confers good protection, but it is impossible to measure T-cell immunity in daily clinical practice.
PP: Immunogenicity in cancer patients undergoing radiotherapy is significantly lower than in healthy individuals,[33] as corroborated by another study on patients with solid tumours.[34] In cancer patients, adverse events from vaccination were minimal, so additional booster doses should be recommended.[34]
Managing high-risk patients with COVID-19 infection is an ongoing challenge. I have a patient with a history of chronic lymphocytic leukaemia (CLL) who remained persistently COVID-19 positive with the Omicron variant. Following antiviral treatment, we observed low immunoglobulin G (IgG) levels and administered intravenous immunoglobulin (IVIg) every four weeks to maintain higher levels, which was effective. Do you have experience with similar cases?
TW: Yes, we call these patients non-eradicators. They test positive for months/years and experience intermittent symptoms. It is extremely important to normalise their IgG levels, as you have been doing, but it does not always solve the issue. Around a third of non-eradicators continue to test positive for SARS-CoV-2. The problem is not resistance; the viral infection persists in body tissues that are inaccessible to any immune response, or to IVIg therapy.
The clinical benefits of antiviral and monoclonal treatments in high-risk groups
Table 2 summarises the antivirals and specific monoclonal antibodies developed to treat early infection with SARS-CoV-2 to prevent severe disease.
How do you use anti-viral medications?
TW: Antivirals are an important early intervention in high-risk groups, irrespective of their vaccination status. Choosing patients who are likely to benefit is important, as is early delivery of the treatment.
BY: In Singapore, oral antivirals such as nirmatrelvir+ritonavir and molnupiravir are readily available, but uptake has been limited. This is probably due to patients seeking help only when the window for effective antiviral intervention has passed.
PP: In Thailand we have access to remdesivir, molnupiravir, and nirmatrelvir+ritonavir. Favipiravir was used but the guidelines no longer recommend it because of a lack of evidence of efficacy.[35] It is also currently in demand for influenza patients.
How do you use SARS-CoV-2 specific monoclonal therapies?
TW: At the beginning of the first Omicron wave, we used tixagevimab+cilgavimab. Tixagevimab+cilgavimab gives months protection of protection rather than weeks but, unfortunately, it is totally ineffective against the newer COVID-19 variants.[36] In Europe, Sotrovimab is recommended and has been shown to inhibit both EG.5.1 and XBB.2.3 variants,[37] and we give it in combination with antivirals, either nirmatrelvir+ritonavir or remdesivir. Even so, patients in high-risk groups still experience elevated mortality rates.
Challenges of enhancing vaccine uptake in those that are most at risk
What is the current vaccination strategy for 2023/2024
TW: In Europe, an annual booster is recommended for people in high-risk groups. The European Commission made the legally binding EU-wide decision to use the monovalent XBB.1.5 updated mRNA vaccines in September 2023.[38] The Pfizer XBB.1.5 vaccine is likely to be used this winter throughout Europe for high-risk groups, and the Moderna XBB.1.5 vaccine will be available for purchase. Both vaccines work against the EG5 variant and XBB.1.9, which is currently on the increase in Europe and data on its efficacy against emerging variant BA.2.86 is encouraging.[39]
BY: The XBB 1.5 monovalent vaccines from both Moderna and Pfizer have been approved in Singapore and have been available since November 2023. Currently circulating variants are sufficiently similar for this updated vaccine to be effective for the next year. though concerns have been raised that BA.2.86 and its descendants such as JN.1 are more immune evasive.[1] The vaccines are free and widely available. Boosters are recommended for high-risk groups, but anyone can access the vaccination if they wish.[3]
PP: Public Health in Thailand is currently trying to procure stocks of the Moderna and Pfizer XBB.1.5 monovalent vaccines. Currently the state continues to reimburse the cost of COVID-19 vaccination, but I anticipate that free vaccines will shortly be limited to high-risk groups only, in line with the influenza vaccination model.
How do we define the high-risk groups for booster vaccination programs?
BY: The recommendations in most regions are similar and sensible. Most favour additional COVID-19 boosters for individuals over 60/65 years and those with comorbidities such as cancer, diabetes, and cardiovascular disease. Boosters should help reduce the risk of hospital admission and prevent complications, as the annual influenza vaccine does.
PP: Should healthcare works be added to the groups who are offered additional booster vaccinations?
BY: That is a good point; the Singapore Ministry of Health has recently updated its recommendations to advise that health care workers, carers in nursing homes and people caring for elderly relatives at home also receive a booster.[40]
How are booster vaccinations administered within the healthcare system?
TW: In Germany, all COVID-19 vaccines are given by physicians as they are reimbursed to do so, while specialists and hospitals are not.
PP: Until recently Thailand had many walk-in vaccination centres but many of these closing. I anticipate we will move to a system in which physicians prescribe and give the COVID-19 vaccination, as they do with influenza vaccination.
BY: In Singapore; vaccines were administered by some GPs but we also had walk-in vaccination centres during the height of the pandemic. Now, as in Thailand, many centres have closed and vaccination is moving back into the realm of the GP, who will be responsible for advising individual patients on the benefits of booster vaccination.
In high-risk groups, it is also important for the specialist providing the patient's care to discuss with their patients the importance of being vaccinated, recommending additional booster doses, even if these are administered by their GP.
TW: We provide vaccinations to all patients in our transplant centre; they do not need to return to their GP.
What strategies are needed to raise awareness of the value of booster vaccinations in high-risk groups?
TW: In Germany, I think that a renewed focus on public awareness regarding vaccination is necessary. Wider outreach via social media and television, as well as educational programmes tailored for high-risk populations, are essential to increase vaccine uptake. Compared to one or two years ago, such efforts have declined significantly. France, which advertises vaccination on TV every evening, has significantly higher vaccine uptake.
BY: In Singapore the Ministry of Health has been leading the conversation in terms of promoting vaccination to the correct groups and ensuring that vaccines are as accessible as possible. That is now changing as COVID-19 becomes endemic, and the onus will be much more on primary care and hospital specialists to provide information to vulnerable patients under their care.
Acknowledgements
Dr Kathryn Senior, independent medical writer, helped draft this article.