The covid-19 vaccines—with defined mechanisms of action and dosing schedules—that regulatory bodies have approved for use worldwide have been a great success. [1,2] The vaccines’ effectiveness in preventing symptomatic and serious illness in individuals has been shown in phase III randomised clinical trials. Cohort studies regarding decreases in hospital admissions and deaths from covid-19 by induction of protective immunity are now starting to be reported, although lockdowns in many countries may be a confounding factor in these studies. [3,4,5,6] Recent evidence also shows that several vaccines are able to interrupt virus transmission. [6,7,8] The vaccines’ success indicates that they can contribute to helping the world overcome the SARS-CoV-2 pandemic. At the moment, however, the benefits of vaccination are grossly and unevenly distributed, with high and middle income countries (HMICs) outstripping, and leaving behind, low income countries (LICs). [9]
In early February 2021, not a single dose had been administered in 130 poorer countries. By 7 December 2020, HMICs, which account for only 14% of the world’s population, had bought up more than half of the leading vaccines. [10] Widespread blanket covid-19 immunisation in 85 poor countries will not take place until 2023. Globally, many HMICs have pipeline access to billions of doses of vaccines, whereas most others currently have no access at all or to a limited degree only. [10] COVAX—a global initiative aimed at equitable access to covid-19 vaccines led by UNICEF, Gavi (the Vaccine Alliance), the World Health Organization, the Coalition for Epidemic Preparedness Innovations, and others—was set up to help overcome global disparities in vaccine acquisition, but demand for vaccines is likely to outstrip supply in LICs for the foreseeable future. [10,11] It is noteworthy that throughout March 2021 sporadic small scale supplies of covid-19 vaccines have been delivered to LICs by Covax, alongside those already donated by China and Russia.
Demand outstripping vaccine supply has happened even in high income countries. Some have adopted strategies to increase the number of people who can be vaccinated by means of evidence based modifications of vaccine RCT schedules with the approval of regulators. By contrast, the UK has introduced a delayed second dose of covid-19 vaccine(s) to help overcome shortages. [12] The UK’s gamble is to bridge the gap between demand and supply while protecting as many people as quickly as possible. Views on the risks associated with such a strategy differ, particularly for the mRNA vaccines (ie Pfizer-BioNtech and Moderna). [13]
Natural exposure—resulting in asymptomatic or symptomatic infection and recovery from SARS-CoV-2—correlates with the induction of T cell and B cell immunity and the acquisition of immunological memory. [14] Some recent small studies suggest that antibody positive individuals who recover from symptomatic covid-19 have well primed immune responses that can be boosted effectively by a single vaccination to give potent, and possibly longer lasting, immunity than natural infection. [15,16,17] However, most cases of covid-19 are known to be asymptomatic or minimally symptomatic. People with such mild infection are known to produce lower levels of antibodies. Recent pre-print studies found that antibody levels are not well boosted after a first dose of mRNA covid-19 vaccines in those individuals. [16,18] Suggested strategies of using antibody screening of community based asymptomatic individuals may therefore not result in sufficient protection after a single dose only. [19]
Therefore, for HMICs with access to vaccines and LICs aiming to source vaccines, evidence that people with a history of a positive clinical diagnosis for covid-19 before vaccination show good responses to a single vaccine dose could support a strategy for increasing vaccine coverage that can be implemented worldwide. [15,20] This could help alleviate the imbalance between supply and demand without adopting procedures not supported by the evidence, such as the UK’s strategy of delaying the second dose of the Pfizer-BioNTech mRNA vaccine by up to 12 weeks.
Essentially, the strategy would survey individuals by a structured questionnaire, at the time of their first vaccination, to ascertain whether they have had symptomatic virus infection, confirmed by a clinical diagnostic test or otherwise. In case of a positive response, those people would be given a single vaccine dose to induce protective immunity. [20] Subsequently these individuals would be treated like all those who have had the standard scheduled immunisation doses e.g two doses with regard to considering boosters as deemed necessary based on longevity of protective immunity.
If such a strategy were to be implemented, it would need to be rapidly and rigorously evaluated through a large scale randomised controlled trial, studying whether effectiveness varies by demographic variables, severity of and time since infection, and pre-existing conditions.
Such a strategy sounds simple, but clearly raises other logistical issues, such as generating, and having staff to evaluate questionnaires in real time, and incorporating this into a mass vaccination rollout, especially in view of the disparities between the HMICs and LICs. Specialists in these areas would need to examine this proposal in their environments with reference to their infrastructures, including access to staffing and IT systems. Ideally, rapid early small-scale trials should also be considered to establish the feasibility of adopting such a strategy, and further evidence should be collected to confirm whether a single dose offers sufficient immunity in individuals who have already had symptomatic covid-19 infection.
Herb F Sewell, emeritus professor of immunology and consultant immunologist, University of Nottingham
John F R Robertson, professor of surgery and consultant surgeon, University of Nottingham
Marcia Stewart, social care professional and emeritus academic, De Montfort University
Denise Kendrick, professor of primary care research and general practitioner, University of Nottingham
The authors declare the following other interests: None
Acknowledgement: Sheila Bird, Formerly Programme Leader, MRC Biostatistics Unit, University of Cambridge for helpful discussions and reading of drafts.
References:
1) Teijaro, J.R., Farber, D.L. COVID-19 vaccines: modes of immune activation and future challenges. Nat Rev Immunol (2021). https://doi.org/10.1038/s41577-021-00526-x
2) Mahase, E. Covid-19: Where are we on vaccines and variants? https://www.bmj.com/content/bmj/372/bmj.n597.full.pdf
3)Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med.384, 403–416 (2021)
4) Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med.383, 2603–2615 (2020).
5) Voysey, M. et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet397, 99–111 (2021)
6)Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Eng J Med. 2021. doi: 10.1056/NEJMoa2101765. Epub ahead of print. PMID: 33626250
7)Chodick G, Tene L, Patalon T, et al. The effectiveness of the first dose of BNT162b2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real- world evidence. MedRxiv preprint server. https://www.doi.org/10.1101/2021.01.27.21250612 (accessed February 15, 2021).
8)Amit S, Regev-Yochay G, Afek A, et al. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. Lancet. 2021. doi: 10.1016/S0140-6736(21)00448-7. Epub ahead of print. PMID: 33610193.
9)World Health Organization. WHO Concept for fair access and equitable allocation of COVID-19 health products. Final working version 9 September 2020. Geneva, Switzerland: World Health Organization, 2020. https://www.who.int/publications/m/item/fair-allocation-mechanism-for-covid-19-vaccines-through-the-covax-facility.
10) So AD, Woo J. Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis. BMJ. 2020 Dec 15;371:m4750. doi: 10.1136/bmj.m4750.
11) COVAX. Commitment Agreements, September 30, 2020. https://www.gavi.org/sites/default/files/covid/pr/COVAX_CA_COIP_List_COVAX_PR_30-09.pdf.
12) Department for Health and Social Care. Letter to the profession from the UK Chief Medical Officers regarding the UK COVID-19 vaccination programmes. Dec 21, 2020. https://www.gov.uk/government/ publications/letter-to-the-profession-from- the-uk-chief-medical-officers-on-the-uk- covid-19-vaccination-programmes/ letter-to-the-profession-from-the-uk-chief- medical-officers-regarding-the-uk-covid-19- vaccination-programmes (accessed Feb 18, 2021).
13) Robertson J F, Sewell H F, Stewart M. Delayed second dose of the BNT162b2 vaccine: innovation or misguided conjecture? www.thelancet.com Published online February 19, 2021 https://doi.org/10.1016/S0140-6736(21)00455-4
14) Dan JM, Mateus J, Kato Y, Hastie KM et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021 Feb 5;371(6529):eabf4063. doi: 10.1126/science.abf4063. Epub 2021 Jan 6. PMID: 33408181
15) Ebinger, J.E., Fert-Bober, J., Printsev, I. et al. Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2. Nat Med (2021). https://doi.org/10.1038/s41591-021-01325-6
16) Demonbreun A R, Sancilio A, Velez M E et al Comparison of IgG and neutralizing antibody responses after one or two doses of COVID-19 mRNA vaccine in previously infected and uninfected persons medRxiv preprint doi: https://doi.org/10.1101/2021.03.04.21252913;
17) Covid-19: People who have had infection might only need one dose of mRNA vaccine, BMJ 2021;372:n308 https://www.bmj.com/content/372/bmj.n308
18)McDade TW, Schrock JM, D’Aquila R, et al. Symptoms of COVID-19 infection and magnitude of antibody response in a large community-based study. medRxiv. 2021:2021.2002.2004.21251170.
19) Manisty C, Otter A D, Treibel T A et al, Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Published Online February 25, 2021 https://doi.org/10.1016/ S0140-6736(21)00501-8
20) T-cell and antibody responses to first BNT162b2 vaccine dose in previously SARS-CoV-2-infected and infection-naive UK healthcare workers: a multicentre, prospective, observational cohort study’ is available at Preprints with the Lancet, here: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3812375