Vaccines are our hope to end the COVID-19 pandemic. Yet, despite the availability of vaccines to fight the pandemic, we are still facing grave challenges and an uncertain future. On one hand, due to the constraints of vaccine supply current COVID-19 vaccination strategies must reserve a large number of doses of vaccines in order to deliver the second dose on time to those who have already received the first dose. On the other hand, there is an urgent need to vaccinate as many people as possible in order to reduce the ongoing substantial community transmission and reduce burden on already overwhelmed health care systems. Postponing the second dose and releasing the doses withheld to give more people a single dose seems to be a solution.
The United Kingdom (UK) announced a change to their schedule for the second dose of the Pfizer-BioNTech COVID-19 vaccine on December 30th, 2020, specifically, extending the interval between the first and the second shots from the previously recommended 21 days (3 weeks) to 84 days (12 weeks) (Department for Health and Social Care, 2020). The major reason for delaying the second dose of COVID-19 vaccine was to address the shortage of vaccines and ensure the number of people receiving the vaccine was maximized – noted as “a reality that cannot be wished away” (Department for Health and Social Care, 2020).
Likewise, during the World Health Organization (WHO) press release on January 5th, 2021, the Strategic Advisory Group of Experts on immunization, known as SAGE, also recommended the delay for administering the second dose of the Pfizer-BioNTech vaccine in the context of a vaccine supply shortage, and suggested that the second dose might be delayed to up to 42 days (6 weeks) (Source).
On January 12th, the National Advisory Committee on Immunization (NACI) of Canada advised that some regions might “maximize the number of individuals benefiting from a first dose of vaccine [i.e., Pfizer-BioNTech vaccine and Moderna vaccine] by delaying the second dose, until further supplies of the vaccine become available, preferably within 42 days of receipt of the first dose” (Source).
Such decisions and recommendations have raised concerns and caused debates. On the same day the UK announced its plan to delay the second dose of COVID-19 vaccine, the British Medical Association (BMA) expressed their objection and called the decision “unreasonable and totally unfair … [and would cause] huge logistical problems” (Mahase, 2020).
On January 1st, 2021, Dr. Anthony Fauci, the director of the United States (US) National Institute of Allergy and Infectious Diseases (NIAID), disagreed with the UK’s move and told CNN that the US would not follow the UK’s lead to extend the interval between doses. He insisted that “We know from the clinical trials that the optimal time is to give it on one day and for Moderna 28 days later and for Pfizer 21 days later” (Source).
On January 13th, a statement (Source) questioning the change in the vaccination schedule, was released by the innovative biopharmaceutical industry, including the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Pharmaceutical Research and Manufacturers of America (PhRMA), European Federation of Pharmaceutical Industries and Associations (EFPIA), Vaccines Europe, Biotechnology Innovation Organization (BIO) and International Council of Biotechnology Associations (ICBA). The innovative biopharmaceutical industry statement indicated that it believes “vaccine deployment strategies should be based on the outcome of these continuing clinical studies and the evolving knowledge” and it supports “adhering to the dosing that has been assessed in clinical trials and urges that any changes from the tested and approved vaccine dosing and vaccination schedules for COVID-19 vaccines should follow the science and be based on a transparent deliberation of the available data.”
All these debates seem to raise more questions. Is there any empirical evidence to support the schedule change for the second dose? If so, what is it? What are the potential challenges and risks for delaying the second dose? The present OE Original, by examining current available evidence, may provide some answers.
1. What can we learn from vaccine trials about changing the schedule of the second dose?
In this section, we looked at the evidence of three major vaccines currently being used, including two mRNA vaccines developed by Pfizer-BioNTech and Moderna, respectively, and one chimpanzee adenovirus-vectored vaccine developed by Oxford-AstraZeneca. These three vaccines were discussed in our previous OE Original: Vaccines for COVID-19: Pfizer, Moderna, and AstraZeneca Race to Finish Line.
Pfizer-BioNTech vaccine and Moderna vaccine
Results about the efficacy and safety of the Pfizer-BioNTech and the Moderna vaccines were both published in the New England Journal of Medicine (Baden et al., 2020; Polack et al., 2020). The Pfizer-BioNTech phase III study was a multinational, single-blinded (i.e., observer-blinded) randomized placebo-controlled trial. Participants were randomly assigned to two doses of either the vaccine or the placebo. The interval between the two doses was 21 days. The Moderna phase III trial was similar to the Pfizer-BioNTech trial in terms of study design except that it was conducted in the US and the interval between the first and second shots was 28 days.
Unfortunately, there was no evidence available in either trial indicating the impact of a change in the schedule of the second dose. The trial did not compare the vaccine efficacy between different dose intervals or between participants receiving only one dose of Pfizer-BioNTech vaccines and those who received two doses.
The trial results of the Oxford-AstraZeneca vaccine were published in the Lancet (Voysey et al., 2021). It combined four ongoing randomized controlled trials (RCTs) conducted in the UK (COV001 and COV002), Brazil (COV003), and South Africa (COV004), which included different spacing between doses (Voysey et al., 2021). The interval between the first and second doses among the four trials varied from 4 to 12 weeks. However, the analysis done by Voysey et al. (2021) only indicated that the vaccine efficacy might not be affected by a longer gap (= 6 weeks) when compared to a shorter interval (< 6 weeks).
There is very limited empirical evidence from vaccine trials which can either support or refute the schedule change for the second dose of vaccines against COVID-19.
2. If we have to change the schedule for the second dose due to vaccine shortage
How effective is just one dose in terms of inducing immunity among recipients?
The Pfizer-BioNTech trial showed a vaccine efficacy of 52.4% [95% confidence interval (CI): 29.5% to 68.4%] after participants had received the first dose and before they received the second dose (21 days between dose 1 and dose 2) (Polack et al., 2020). This vaccine efficacy is likely to be an underestimate because it usually takes 7 to 14 days for the human body to develop immune response, and cases happening within this period might not be due to vaccine inefficiency but because the patients had already infected the viruses upon vaccination (Institut national de santé publique du Québec (INSPQ), 2021). Provided this possibility, a further post-hoc analysis based on the Pfizer-BioNTech trial excluded cases occurring within 14 days of the first dose and saw an increase in vaccine protection — the vaccine efficacy during the period from 14 days after the first dose until the second dose was 92.3% [95% CI: 69% to 98%] (Institut national de santé publique du Québec (INSPQ), 2021).
According to the documents Moderna submitted to the US Food and Drug Administration (FDA), among participants who only received one dose, the vaccine efficacy 14 days after dose 1 was 92.1% [95% CI: 68.8% to 99.1%] (Moderna, 2020). The estimated efficacy of the AstraZeneca vaccine from 22 days after the first dose was 73% (95% CI 48.79% to 85.76%) (Department for Health and Social Care, 2021). All the above data suggest that we might achieve a satisfactory vaccine efficacy (> 50% defined by the FDA) even in the worst case scenario (the lower boundary of the 95% CI) when offering only one dose to the population.
How long will the protection from just one dose last?
Unfortunately, there is no available evidence to determine the duration of efficacy from a single dose of vaccines against COVID-19.
Will delaying the second dose affect the overall vaccine efficacy?
The data from the Oxford-AstraZeneca vaccine indicated that extending the dose interval might not have any negative impact on the overall vaccine efficacy (Voysey et al., 2021). The analysis showed that there was no statistical difference [P = 0.56] between vaccine efficacy more than 14 days after the second shot in participants with < 6 weeks’ interval [vaccine efficacy: 53.4%, 95% CI: -2.5% to 78.8%] between two standard doses [5?×?1010 viral particles] and those with = 6 weeks’ interval [65.4%, 95% CI: 41.1% to 79.6%] (Voysey et al., 2021). However, we could not identify any evidence to answer this question for the Pfizer-BioNTech vaccine and the Moderna vaccine.
Evidence from modelling research
Besides the empirical evidence, a model-based study published in the Annals of Internal Medicine on January 6th evaluated vaccinating as many people as possible by releasing the doses withheld compared to following the standard vaccine release schedule: the flexible strategy and the fixed strategy, respectively (Tuite et al., 2021). The former only reserves one-tenth of the vaccine for the second doses during the first 21 days after the first shot, 90% for the next 21 days, and 50% afterwards, representing a more balanced approach that withholds fewer doses of COVID-19 vaccines. The latter, which reserves 50% of each vaccine installment for the second doses scheduled for 21 days after the first dose, represented the current vaccination policy of the US. The model showed that compared to the fixed strategy, the flexible strategy could prevent the occurrence of an additional 23% to 29% COVID-19 cases assuming a steady vaccine supply of 6 million doses each week.
3. What are the potential risks and challenges for delaying the second dose?
One of the major concerns for delaying the second dose of COVID-19 vaccine is the increased risk of fostering vaccine-resistant virus strains. A preprint released on BioRxiv showed that a COVID-19 viral variant (501Y.V2) has evolved two mutations which could block the effectiveness of antibodies used to treat COVID-19 (Tegally et al., 2020). Another preprint suggested that one of the mutations (a mutation at E484) found in 501Y.V2 could reduce neutralizing antibodies’ ability to block the coronavirus from entering cells more than 10-fold (Greaney et al., 2021).
Some scientists worried that extending the time between the two doses from 21 days to 42 days or even 12 weeks, could create a group of people who have partial immunity developed from their first dose to slow down the viruses and prevent symptoms, yet inadequate to kill the viruses. Viruses with mutations could be incubated among these people (Ledford H., 2021). As Paul Bieniasz, an expert in virus mutation, pointed out, “My concern, as a virologist, is that if you wanted to make a vaccine-resistant strain, what you would do is to build a cohort of partially immunized individuals in the teeth of a highly prevalent viral infection” (Source). More empirical research is required to address this issue.
Some experts are also concerned that extending the interval between the two doses could cause some partially immunized individuals to contract COVID-19 while waiting, and therefore hurt people’s confidence in the efficacy of vaccines (Iacobucci et al., 2021). Additionally, some people may not be back for their second dose if the appointments were postponed for several weeks.
There is very limited empirical evidence which can either support or refute the schedule change for the second dose of vaccines against COVID-19. Uncertainty remains. However, there is one thing that can be certain: More evidence is urgently needed. We must make decisions out of evidence, not fear.
Baden, L. R., et al. (2020). Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine. doi:10.1056/NEJMoa2035389
Barnabas, R. V., et al. (2021). A Public Health COVID-19 Vaccination Strategy to Maximize the Health Gains for Every Single Vaccine Dose. Annals of Internal Medicine. doi:10.7326/M20-8060
Department for Health and Social Care. (2020). Letter to the profession from the UK chief medical officers regarding the UK covid-19 vaccination programmes. Retrieved from 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
Department for Health and Social Care. (2021). Optimising the COVID-19 vaccination programme for maximum short-term impact. Retrieved from https://www.gov.uk/government/publications/prioritising-the-first-covid-19-vaccine-dose-jcvi-statement/optimising-the-covid-19-vaccination-programme-for-maximum-short-term-impact
FDA. (2021). Emergency use authorization (EUA) of the Pfizer-Biontech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). Retrieved from https://www.fda.gov/media/144413/download
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Iacobucci, G., et al. (2021). Covid-19 vaccination: What’s the evidence for extending the dosing interval? BMJ, 372, n18. doi:10.1136/bmj.n18
Institut national de santé publique du Québec (INSPQ). (2021). Strategy for Vaccination Against COVID-19: Postponement of the Second Dose in a Context of Shortage. Retrieved from https://www.inspq.qc.ca/en/publications/3098-vaccination-second-dose-context-shortage-covid19
Ledford H. (2021). How can countries stretch COVID vaccine supplies? Scientists are divided over dosing strategies. Nature, p. 182.
Mahase, E., (2020) Covid-19: Order to reschedule and delay second vaccine dose is “totally unfair,” says BMA. BMJ doi:10.1136/bmj.m4978 pmid:33384299
Moderna. (2020). Vaccines and Related Biological Products Advisory Committee. FDA Briefing Document. Retrieved from https://www.fda.gov/media/144434/download
Polack, F. P., et al. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 383(27), 2603-2615. doi:10.1056/NEJMoa2034577
Tegally, H., et al. (2020). Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv, 2020.2012.2021.20248640. doi:10.1101/2020.12.21.20248640
Tuite, A. R., et al. (2021). Alternative Dose Allocation Strategies to Increase Benefits From Constrained COVID-19 Vaccine Supply. Annals of Internal Medicine. doi:10.7326/M20-8137
Voysey, M., et al. (2021). 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. The Lancet, 397(10269), 99-111. doi:10.1016/S0140-6736(20)32661-1