COVID-19 vaccines: Burning questions from the community and real-world applicability

View a number of questions of interest to the interventional cardiovascular community, as well as the real-world applicability of COVID-19 vaccine trials.

Our consensus:

There is a general agreement to define a vaccine as effective when the rate of efficacy is ≥ than 50% (WHO).
Without head-to-head trials we cannot reliably compare vaccine efficacy. One of the reasons is that vaccine efficacy is based on the risk (or hazard) ratio, which is itself proportional to the rate of symptomatic COVID-19 cases in a given study. Since there is a variation of the event rates (i.e. symptomatic COVID-19) across different studies, the ratio of risk in the vaccine vs. control group, and by extension vaccine efficacy, may be perceived as a study-specific measure of the risk reduction conferred by a study-specific vaccine. 

Therefore, in terms of vaccine efficacy, an emergency authorization of any vaccine with a ≥ 70% demonstrated efficacy seems reasonable:  due to scale of pandemic as many as possible of a population require to be vaccinated and that as soon as possible.
The potential logistic issues - storage temperatures and precautions - are additional arguments to justify this authorisation.

Our consensus:

Delaying vaccination for those who have had a previous infection remains an unresolved dilemma.

• Whether individuals who had symptomatic or asymptomatic COVID 19 infection early in the pandemic mount a sustainable or a sufficient immune response to prevent a second infection is unknown.
• Whether those who had the COVID-19 infection early in the pandemic have a sustained immune response that includes the variants also remains unresolved.

Assessing antibodies for all previously infected individuals, symptomatic and asymptomatic, may better streamline the selection process and allow health authorities to prioritize the vaccination.

Lumley et al, Hospitals Staff Testing Group, noted in their December 23 publication in the NEJM that the presence of anti-spike or anti-nucleocapsid Ig G antibodies was associated with a substantially lower risk of reinfection in the subsequent 6 months.

However, given the logistical and administrative challenges involved in vaccinating whole populations, any calls for increasing the complexity of the vaccine schedule are likely not to be adopted.

As the global second surge rages on, a single/delayed vaccine dose strategy has recently been proposed.
Based on the phase 2a randomized data assessing the reactogenicity, safety and immunogenicity of the Moderna (https://www.fda.gov/media/144434/download) vaccine, 600 individuals were enrolled (300 above and 300 below the age of 55 years). Two doses 50mcg and 100mcg were evaluated. The immune response was assessed by bAB and nAB ELISA assays. The immune response was comparable in both doses. The older age had a slightly lower response compared with the younger age at 28 days.

Potentially and based on limited phase 2 data, giving a reduced dose could be a  more plausible alternative to delaying the second dose (which remains an untested approach).
However, the most critical limitation is the small numbers that don’t permit subgroup analysis of high-risk individuals or transmission during the surge.
Overall, the decision of governments to advocate a single/delayed vaccine dose strategy is outside of our conventional interpretation of scientific data.
Specifically, it becomes an ethical judgement, where healthcare leaders have to weigh the potential ‘risk’ of reduced vaccine efficacy (or mutant selection) against the ‘benefit’ of a hoped-for reduction in deaths and an overwhelming of healthcare systems. This strategy could potentially erode public trust in the healthcare system and lead to vaccine hesitancy.

 

Real World Applicability of the ChAdOx1 nCov-19 vaccine and the BNT1626b2 mRNA Vaccine

The WHO has suggested that a minimum criteria for any vaccine against Covid-19 should be a “clear demonstration of efficacy with a ~ 50% point estimate”(1) which can be assessed by disease, severe disease or transmission endpoints. Clearly with a vaccine efficacy of 70.4% overall the ChAdOx1 nCov-19 vaccine meets this criteria however still awaits regulatory approval. Similarly the BNT162b2 mRNA vaccine has an efficacy of 95.0% overall, again awaiting regulatory approval in most countries however in use in the United Kingdom and approved in the USA.Both trials used confirmed Covid-19 cases as their primary efficacy outcomes at least 7 days after the second dose of the vaccine for the BNT162b2 mRNA and 14 days after the second dose for the ChAdOx1 nCov-19 vaccine. These timelines post vaccination are important as although in the immediate phase of vaccination it is unlikely that restrictions will be lifted as the process continues further evaluation will be required to determine if individuals should maintain strict social distancing post vaccination until either 7 or 14 days has passed post their second dose.

Studying efficacy between diverse races and ethnicities and higher and lower income countries

The ChAdOx1 nCov-19 vaccine studies included diverse races and ethnicities in both high and upper-middle income countries with similar results in both countries for the SD/SD schedule. This is an important finding as vaccine efficacy has been shown to differ between higher and lower income countries although this seems to affect oral rather than parenteral vaccines (2). Interestingly in the BNT162b2 mRNA vaccine there appeared to be decreased vaccine efficacy in Brazil (87.7%, CI 8.1-99.7) compared to Argentina (98.2%, 95%CI 83.3-99.9) and the USA 94.9% (88.6-98.2%) understanding this is of interest to determine if there are modifiable factors or if an alternative vaccine may be more suitable in this population.

Longer follow-up required to determine if booster vaccination will be required for specific subgroups

There were relatively few older adults (>55 years, 1418, 12.1%) included in the ChAdOx1 nCov-19 analysis due to the design of the trials included. Given that vaccine efficacy for older adults is reduced due to decreased immunogenicity (3) further evaluation is required to determine if a modified vaccine schedule is required for this group. Of note none of the subgroup who received the LD/SD schedule which appears to have increased efficacy were > 55 years. As the risk of severe Covid-19 increases with age further evaluation of the efficacy of the vaccine as well as the LD/SD schedule in this group is required.  In the BNT162b mRNA vaccine trial approximately a quarter of all participants were over the age of 65 with similar efficacy to the younger population implying that at least for this vaccine a modified schedule is not required for the older population. Longer term follow up will be required to determine if this efficacy persists in the population as a whole as well as the older population or will further booster vaccination be required for specific subgroups.       

Safety in pregnancy unknown due to the exclusion of pregnant women in trials

Both trials excluded pregnant women therefore the safety in pregnancy is unknown. Flu vaccination and pneumococcal vaccination are strongly recommended during pregnancy due to the potential to decrease risk to the fetus and infant in the first months of life. Currently recommendations with regard to pregnancy are mixed with the UK regulatory authorities recommending against vaccination during pregnancy and avoiding pregnancy for at least two months post vaccination (4). On the other hand the Society for Maternal Fetal Medicine have been advocating for the inclusion of pregnant women in vaccine trials due to their status as at high risk of developing severe Covid-19 (5). Similarly there is no data available with regard to the safety or efficacy of either vaccine in children or adolescents.

Low numbers of patients with significant co-morbidities included

Overall there were low numbers of patients with significant co-morbities in both trials with approximately 10% cardiovascular and respiratory disease in both studies. Given that these are a higher risk group their inclusion is to be commended however severe or uncontrolled co-morbidities were excluded, given this group are at increased risk of severe Covid-19 it is of interest to assess the efficacy in this group. Both vaccines have good safety profiles in their phase 3 trials however less common side effects may be recognised during phase 4.Key advantages of the ChAdOx1 nCoV-19 vaccine are the ability to store the vaccine at standard fridge temperatures 2-8°C allowing transport and storage in the standard health care systems. In contrast the BNT162b2 mRNA Covid-19 vaccine requires transport and storage at -70±10°C making mass vaccination programmes more difficult particularly in less well developed healthcare systems.

Facing the challenges of mass vaccination programmes

Agreements have been formalised to supply the ChAdOx1 nCov-19 vaccine on a not for profit basis worldwide during the pandemic and in low and middle income countries in perpetuity. This will allow a more equitable access to vaccination worldwide not withstanding the challenges associated with mass vaccination programmes in LMICs. The BNT162b2 mRNA vaccine in contrast is being supplied on a for profit basis, meaning accessibility in LMICs may be limited. Mass vaccination programmes are generally accepted in two circumstances; 1) to rapidly increase herd immunity in the context of an outbreak limiting morbidity and mortality; 2) to accelerate disease control when introducing a new vaccine into the routine vaccination schedule. Covid-19 clearly fits into a category of disease suitable for mass vaccination however estimates suggest there will be only 2.6-3.1 billion vaccines available in 2021 leaving > 50% of the world population without vaccination.

Finally, vaccine hesitancy may limit optimal uptake of the vaccine, both groups who have vaccine hesitancy to all vaccination as well as those with specific concerns related to the Covid-19 vaccinations. Previous surveys have shown that approximately 70% of an international sample would accept vaccination against Covid-19 (6).Overall both vaccines appear efficacious and safe in the groups in whom they have been tested. Further evaluation of the vaccines is required particularly in the older, multimorbid population who are at increased risk of severe Covid-19.

References

1. Organization WH. WHO target product profiles for COVID-19 vaccines. Version; 2020.
2. Church JA, Parker EP, Kirkpatrick BD, Grassly NC, Prendergast AJ. Interventions to improve oral vaccine performance: a systematic review and meta-analysis. The Lancet Infectious Diseases. 2019 Feb 1;19(2):203–14.
3. Oh S-J, Lee JK, Shin OS. Aging and the Immune System: the Impact of Immunosenescence on Viral Infection, Immunity and Vaccine Immunogenicity. Immune Netw [Internet]. 2019 Nov 14 [cited 2020 Dec 11];19(6). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943173/
4. COVID-19 vaccination: information for healthcare practitioners [Internet]. GOV.UK. [cited 2020 Dec 14]. Available from: https://www.gov.uk/government/publications/covid-19-vaccination-programme-guidance-for-healthcare-practitioners
5. Media BK-K. Publications & Guidelines | SMFM.org - The Society for Maternal-Fetal Medicine [Internet]. [cited 2020 Dec 14]. Available from: https://www.smfm.org/publications/339-society-for-maternal-fetal-medicine-smfm-statement-sars-cov-2-vaccination-in-pregnancy
6. A global survey of potential acceptance of a COVID-19 vaccine | Nature Medicine [Internet]. [cited 2020 Dec 14]. Available from: https://www.nature.com/articles/s41591-020-1124-9 

Authors

Date of publication: 13 January 2021