As our group consisted of infectious disease experts and contributors to national vaccination policies in our respective countries, we therefore considered the applicability and consistency of these findings against the limited data available for SEA and shared our recommendations on strategies for future vaccination programs.
Insights on Safety of Available Vaccines. Belief in the overall safety of these vaccines is naturally of paramount importance and whilst the benefit/risk profile of the approved vaccines has been confirmed by regulators worldwide and further established through their extensive global deployment, a small number of ARs have created disproportionate concerns; in particular, thrombotic events with adenovirus vector vaccines and myocarditis or pericarditis with mRNA-based vaccines. While a small increased risk of thrombosis with thrombocytopenia syndrome (TTS) or venous thromboembolism (VTE) with thrombocytopenia (TCP) has been observed after the first dose of AZD1222 (8.1 cases per million doses), much lower rates occurred after a second dose (2.3 cases per million doses).33 Importantly, these rates were similar to background pre-pandemic rates of autoimmune heparin-induced TCP, and were also within the estimated background rates for unvaccinated populations,34 as well as being much lower than TTS-like events due to COVID-19 infections (VTE with TCP was 195.9 events/million patients).33,35 Concerns of reduced platelet levels and venous and arterial thromboses in cerebral veins also arose with AZD1222. Yet, the rates of major arterial or venous thrombotic events were not increased in adults 70 years or older36,37 by primary vaccination with either AZD1222 or BNT162b2. In adults younger than 70 years, a small increase in the excess risk of intracranial venous thrombosis and hospitalisation with TCP after primary AZD1222 vaccination (0.9 to 3.0 events/million) is far outweighed by its reduction of COVID-19 mortality and morbidity. AZD1222 was also thought to be associated with cerebral venous sinus thrombosis (CVST),38 but the rate of CVST events in the four weeks following a primary dose were comparable to the rates at 90 days before vaccination. Nevertheless, given the many doses of vaccines now administered globally, CVST following a first dose of AZD1222 is still a rare clinical event and causality Is difficult to establish.39
In one study from a vaccine AR reporting system in the US using primarily mRNA vaccines,40 the occurrence of most severe ARs was associated with sex, age, day of onset, and vaccine platform, with elderly individuals experiencing higher rates of thrombosis and ARs affecting the heart, blood, and nervous system. Conversely, younger individuals had a higher incidence of inflammation-related ARs such as Bell’s palsy, myocarditis or pericarditis and lymphadenopathy, as well as convulsions or seizures. Nevertheless, the occurrence of severe ARs (e.g., Guillain-Barré Syndrome, deep-vein thrombosis, lymphopenia) were slightly lower than baseline for mRNA-1273 and significantly lower than baseline for BNT162b2. mRNA-based vaccines are also associated with a rarer but higher rate of vaccine-associated anaphylaxis in females than males,41,42 and with the rare occurrence of myocarditis and pericarditis, particularly in adolescent and young adult males.43 In Europe, myocarditis has been reported at over 26 to 57 events/million within one week of mRNA vaccination while in the US reported events estimated at a rate of 1−40.6 cases/million second doses of mRNA vaccines in males aged 12−29 years.44,45
CoronaVac, which is widely used across Asia, was evaluated in Brazilian healthcare workers,46 where no severe ARs were attributed to the vaccine. While some of the initial concerns with these events led to some usage restrictions and label updates for different vaccines, the current body of evidence suggests these events are very rare and quite manageable through improved diagnosis and treatment algorithms in most circumstances with a very favourable benefit/risk profile for all COVID-19 vaccines.
Similarly, there may be concerns regarding safety of booster doses. However, the recent phase II RCT, COV-BOOST,47 evaluated seven types of vaccines as a third or booster dose after a primary series of AZD1222 or BNT162b2, and found expected ARs due to inflammation, such as injection site pain, fatigue and headaches, all of which were well-tolerated. Importantly, social media amplification of reports about vaccine-related ARs has led to excessive worry among people even when doctors may be unconcerned.48 We acknowledge that SEA countries do not yet have safety data on boosters, which is a gap that needs to be addressed in future studies. However, evidence available elsewhere and in COV-BOOST do not indicate any serious concerns. Healthcare providers and policymakers must address this by ensuring that accurate, updated data are widely and frequently shared with the general public and that safety concerns are not simply dismissed.
Insights on Waning of VE or Duration of Protection. Our analysis consistently confirmed a high VE at preventing hospitalisations and deaths, at comparable levels across all vaccines, regardless of VOC (excluding Omicron). Numerous reports of waning antibody levels49-51 have driven the implementation of booster doses in many countries, based primarily on the associated waning of protection against mild infections, manifesting as breakthrough cases in vaccinated individuals.52,53 Importantly, despite declining antibody levels, we found high and sustained VE against hospitalisations and deaths for AZD1222 and mRNA-based vaccines up to 140 days, with limited waning observed when data enabled informed assessments (Figure 4).
Insights on Correlates of Protection. We emphasise the importance of being aware of how VE is measured and the clinical outcomes by which waning is quantified, in order to understand why vaccine-induced immunity declines against SARS-CoV-2 infection or COVID-19. Currently, protection is assumed through levels of neutralising antibodies49 but the precise levels required to achieve this are still being established.54 Neutralising antibodies provide initial protection against overall infection but do not provide sterilising immunity, limiting their impact on COVID-19 transmission.49 Phase III efficacy trials for AZD1222 and mRNA-1273 both correlated the levels of immunoglobulin G (IgG) antibodies against a virus’ spike or receptor-binding domain to protection against symptomatic infection.55-58 But in the real-world, high levels of antibodies were seen in some healthcare workers with breakthrough infections, and evidence is insufficient to support using antibody levels to predict potential infections.59-63 Moreover, cell-mediated immunity against COVID-19 can be induced by vaccines even when antibody-mediated mechanisms are lacking.64 RWE indicates that COVID-19 vaccinations conferred a high level of protection against hospitalisation and death, and for at least 20 weeks after a second dose 2,17,63-65 despite VE waning against infection within six months of vaccination.68 Breakthrough infections suggest that protection against infection may not be sufficiently durable, and that further vaccine doses are needed to support that clinical objective. With the emergence of Omicron, this waning is accentuated and underscores the need for the completion of primary series vaccinations and/or the addition of booster doses to maintain high levels of protection, especially against severe COVID-19 outcomes.2 The minimal waning observed in our review against the Delta variant reaffirms our collective belief that VE against severe outcomes is not well correlated with antibody levels, and is indeed dependent on cellular immunity.69,70 Consequently, T-cell responses may be a stronger indicator of protection against severe disease than neutralising antibodies54,71-73 and we suggest that all the current vaccines induce strong T-cell responses that prevent severe disease. Thus, boosting with viral vector vaccines (which are more widely available and logistically easier to distribute than mRNA vaccines) should increase protection for un-boosted populations, regardless of the primary vaccine.
Insights on the Impact of the Omicron Variant. Previous data suggests high and comparable VE against symptomatic infections by previous variants,74-77 but data for Omicron is still accumulating. RWE data from the UK78 provided a robust comparison of VE against Omicron and Delta for the vaccines most used there.79 Compared to Delta, VE against symptomatic disease due to Omicron declines substantially after two-dose schedules of AZD1222 or BNT162b2, and wanes more quickly over time than for Delta, starting from 15 weeks after the second dose,79 consistent with what has been observed elsewhere.80 Similarly, VE against hospitalisations due to Omicron drops to 65% (range: 45% to 85%) or 70% (range: 55% to 90%) from 24 weeks after two doses of AZD1222 or BNT162b2, respectively. A high VE against Omicron hospitalisations is restored by homologous or heterologous boosters, yet VE waning appears to occur more quickly over time compared to Delta.2,79 Importantly, with respect to Omicron, VE against overall symptomatic and serious outcomes is highly comparable for two and three dose schedules (homologous and heterologous) of AZD1222 and BNT162b2, and consistent with our review, irrespective of variant and clinical outcome.
An additional consideration, given the very high rate of infections globally, relates to the hybrid protection offered by vaccines in people with a history of COVID SARS-CoV-2 infection. Emerging data suggests that previous natural infections of SARS-CoV-2 are 56% effective against Omicron variant reinfections and 88% effective against severe, critical or fatal COVID-19.81 Recent data from more than 200,000 Brazilians, showed that for people who already had COVID-19, both BNT162b2 and AZD1222 offered 90% effectiveness against hospitalisation and death, consistent with the equivalent protection observed above (>89%, Figures 2 and 3).82 The same study reported that the CoronaVac vaccine provided 81% protection while one dose of the Johnson & Johnson adenovirus-vectored vaccine provided 58% protection following infection.82