Neutralising antibody immunity likely to fall with delayed dose, say these authors

There is ongoing debate about the UK government’s decision to delay the second dose of the Pfizer/BioNTech vaccine until 12 weeks after the first dose, instead of following the recommended dosing interval of 21 days. [1] Our recent BMJ opinion piece questioned the wisdom of the delay. [2] Sheila Bird, co-author of this piece, former programme leader at the Medical Research Council Biostatistics Unit at the University of Cambridge, and a member of the Royal Statistical Society’s covid-19 taskforce, has called for the UK’s policy decision to be evaluated using tilted randomization to assign one quarter of people to receive their second dose at 21 days after the first. Bird has written to Matt Hancock, secretary of state for health and social care, asking him to investigate the effects of extending the gap between doses.

The UK’s strategy to delay the second dose of both the Oxford/AstraZeneca and Pfizer/BioNTech vaccines is so that more people can be vaccinated with their first dose rather than giving a smaller number of people both doses. The hope is that this will save more lives. There are also supply and delivery pressures with the vaccine rollout, although this has not been disclosed as a reason for the dosing delay. 

Public health, medical, and scientific support has been divided. Support for a “finely balanced decision” has come from speciality medical royal colleges, the Academy of Medical Sciences, and the British Society of Immunology. The NHS currently faces enormous pressures from an unrelenting covid-19 pandemic and critical care is in crisis. [3] Therefore vaccinating as many people as possible, and as soon as possible is of great urgency. However, support for delaying the second dose has not always addressed the supply issues and scientific concerns underpinning the case for delaying the second mRNA dose. Some scientists have opposed the delay, especially to the Pfizer vaccine, due to a lack of evidence of effectiveness and potential risks, both personally to individuals vaccinated in this way and to the population at large.

International organisations such as the Centre for Disease Control (CDC), the World Health Organization (WHO), and regulatory bodies such as the Food and Drugs Administration (FDA) in the US; and the European Medicines Agency (EMA) have advised that the vaccination schedules, as defined from the published peer reviewed studies from Pfizer/BioNTech and Moderna (the other mRNA vaccine), should be followed (respectively 1/22 day and 1/29 day first/second dose vaccinations). [5] The German and US governments have recently stated that they do not intend to delay the second covid-19 vaccine shot and Pfizer and Moderna do not support the delay strategy. 

The effect that the changed dosing and the ensuing debate have had on the general population is important. The pandemic has understandably led to a range of emotions from altruism to anxiety, fear, and potential for increased vaccine hesitancy due to confusion about mixed messaging and anger about delays. General practitioners and other healthcare professionals have also indicated disquiet about fractured doctor-patient relationships and a breach of implicit consent by delaying the second dose after patients have consented to have the vaccine. The government has since said that patients already booked in for their second dose could stick with the original appointment, but there were considerable administrative and practical challenges to accommodate the new delay strategy. [6]

Continued monitoring of scientific developments must be used to guide, inform, and if necessary, revisit policy decisions. Scientific method matters, especially for a health strategy based on assumptions, extrapolation from limited data, and undisclosed modelling.

Newly published data on the Moderna vaccine, a similar mRNA vaccine to the Pfizer/BioNTech vaccine, provide new insights that should impact our thinking about the wisdom of the UK’s delayed second dose strategy. 

A new letter in the New England Journal of Medicine (NEJM), published on the 7 January suggests that the long term efficacy of Moderna’s mRNA vaccine, as monitored by serial neutralizing antibody(Nab) levels, even after the standard two dose schedule, may be less than hoped. [7] The letter reports a follow up of results to an earlier study in the NEJM. 

The NEJM letter reported on a group of 34 healthy participants, all of whom had received the two doses of the mRNA vaccine: Nab levels were analysed from the administration of the first dose, through the second dose at 29 days out to 119 days. Neutralizing antibodies were monitored. The peak after the first dose was modest and the fall in neutralising antibodies significant between days 15-21. Indeed, by 28 days, all participants’ Nab levels had fallen to very low levels. The second dose produced a larger secondary immune response which subsequently also decreased, although over a longer time period of a few months. This decrease was more pronounced in the participants in the 56-70 and 71+ years age groups and suggests that, in the older age, the duration of neutralizing antibodies from the Moderna vaccine will be shorter. This questions whether they will be sufficient to protect older citizens beyond a year. Given these are the age groups most at risk of severe covid-19, the data in the NEJM letter suggest that annual vaccination may be required. These data can reasonably be used to inform thinking about deferral of the Pfizer/BioNTech second dose as it is also a mRNA vaccine, this time with the second dose at 22 days. 

These two are the first mRNA based vaccines to be used therapeutically in humans. The number of individuals who contributed to sequential testing of Nab response was small (at most 15 per age-group), so we recognise the limitations of these data. However, they are the most recent data available on Nab induction and duration in humans using mRNA vaccines. The UK, in particular, should be geared up to augment this evidence base. The marked decrease of Nab reported in all age groups at 29 days (i.e. at the time of 2nd dose) is a salutary point to note, given the UK’s strategy for deferral of the 2nd mRNA dose out to 85 days. 

We recognise that Nab is only one contributory arm of protective immunity. [8] Nevertheless, the NEJM letter on a very similar mRNA vaccine to the Pfizer/BioNTech is of concern in respect of: i) the level of personal protection a single dose offers an individual (due to the marked fall in Nab before a second dose), so that extending to 12 weeks may increase infection-risk; ii) the challenge it poses for the undisclosed modelling that the UK government has relied upon to justify altering a proven efficacious standard two dose schedule; and iii) the risk it raises, from a population perspective, of enhancing virus “escape mutations” associated with suboptimal immunity, which could have potentially severe consequences, including nullifying vaccine efficacy. [9,10] A further concern is that these significant decreases in Nabs are despite the Moderna vaccine dose having a higher concentration of mRNA than the Pfizer dose (100ug versus 30ug respectively).

In our view, all of these reasons should make the government reconsider their strategy. If they are determined to continue with the delayed second dose, then a robust randomized evaluation is urgently required. Furthermore, if there is an apparently plentiful supply of the AstraZeneca/Oxford vaccine, which is being rolled out at pace and for which there is a scientific basis for a delay in second dose, is there really a need for the mRNA delayed strategy?

The current UK strategy with the Pfizer mRNA vaccine is, in our view, a non-randomised, uncontrolled population experimental study without pilot data. The Joint Committee on Vaccination and Immunisation (JVCI) and Public Health England should be prepared to revisit and, if necessary, reverse their decisions based on emerging scientific evidence. At the time of writing a statement released by Israeli officials has indicated that “real world” analysis of 200,000 people age >60 years, who have had the first dose of the Pfizer vaccine, shows efficacy of 33%, far less than the 89% stated by the JCVI. These new real world data suggest that the UK should reconsider the decision to delay the second dose of the Pfizer/BioNTech.

Herb F Sewell, Emeritus Professor of Immunology and Consultant immunologist, University of Nottingham.

John FR Robertson, Professor of Surgery and Consultant Surgeon, University of Nottingham. 

Marcia Stewart, Social Care professional and emeritus academic BA(Hons) De Montfort University.

Denise Kendrick, Professor of Primary Care Research and General Practitioner, University of Nottingham.

Sheila M Bird, formerly programme leader at the MRC Biostatistics Unit in Cambridge.

Competing interests: None declared

Declaration of interests: All authors are current or intended recipients of covid-19 vaccines. SMB and HFS have served on UK Medicines Commission from 1990s and 2000s respectively. Both have doctors as family members.

References:

1) Iacobucci G, Mahase E. Covid-19 vaccination: What’s the evidence for extending the dosing interval? BMJ 2021; 372 :n18

2) Robertson JFR, Sewell HF, Stewart M, Kendrick, Agius RM Covid-19 vaccines: to delay or not to delay second doses. https://blogs.bmj.com/bmj/2021/01/05/covid-19-vaccines-to-delay-or-not-to-delay-second-doses/ 

3) British Society for Immunology. Statement on covid-19 vaccine dosing schedules. https://www.immunology.org/policy-and-public-affairs/briefings-and-position-statements/COVID-19-vaccine-dosing-schedules.

4)  Covid-19: Health and social care staff must be vaccinated now, says BMA BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n60 (Published 08 January 2021) Cite this as: BMJ 2021;372:n60 

5) EU says interval between Pfizer vaccine doses should be respected. Reuters. 4 Jan 2020. https://www.reuters.com/article/us-health-coronavirus-ema-pfizer-idUSKBN2991Z3.

6) Mahase E Covid-19: Order to reschedule and delay second vaccine dose is “totally unfair,” says BMA. BMJ 2020;371:m4978. doi:10.1136/bmj.m4978 pmid:33384299

7) Widge AT, Rouphael NG, Jackson LA,et al. Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination.  N Engl J Med. 2021 Jan 7;384(1):80-82. doi: 10.1056/NEJMc2032195.  

8) Sewell HF, Agius RM, Kendrick D, Stewart M. Covid-19 vaccines: delivering protective immunity: Evidence supports both T and B cell responses to the three leading vaccines BMJ 2020;371:m4838  http://dx.doi.org/10.1136/bmj.m4838 

9) https://www.sciencenews.org/article/coronavirus-covid-19-vaccine-delay-second-dose-dangerous-strains

10)  https://healthpolicy-watch.news/80792-2/ UK Delay of Second COVID-19 Vaccine Dose – A Risky Strategy That Could Give Rise To More Virus Mutations, Some Experts Warn.