Where is the evidence that extending the dosing interval for the Pfizer mRNA vaccine from 3 weeks to 12 weeks is effective and safe?
Dear Editor
The four Chief Medical Officers (CMOs) of the United Kingdom and the Deputy CMO for England wrote to the profession on 31 December 2020 to explain their rationale for the dosing schedule for the Oxford vaccine and the change to the dosing schedule for the Pfizer vaccine, to maximise the public health benefits of the vaccine roll-out this winter (1). They supported their arguments with a report from the Joint Committee on Vaccination and Immunisation (JCVI) Optimising the COVID-19 vaccination programme for maximum short-term impact, 31/12/20 (2).
Table 1, Annex A of the report tabulates vaccine efficacy (VE) for the Pfizer vaccine at 15-21 days, 22-28 days and 15-28 days after the first dose (2). The VE at 15-28 days (one week either side of the booster dose on day 22) is 91% (95%CI 74-97). The post-hoc analysis behind this estimate preserves randomisation, is based on apparent reasonable assumptions about time lags before a clinical response to vaccination and is supported by data-derived evidence for the separation of symptomatic Covid-19 incidence curves in the two trial arms (3). Such a high VE so early is reassuring, particularly as the lower bound of the 95% confidence interval for the Pfizer vaccine at 15-28 days is 74%. Although the booster on day 22 may have some effect before day 28, in line with a reported increase in 50% neutralizing antibody titre between days 21 and 28 (4), a VE of 89% (52-97) at 15-21 days is also reassuring (2).
The JCVI present a convincing argument that most of the benefit of the Pfizer vaccine occurs early and that we can anticipate a greater public health benefit in the short term if we accelerate recruitment by postponing the booster and vaccinating twice as many people with a single dose initially (2).
But what then? Patients will be reassured that initial protection with the first Pfizer vaccine dose alone is almost as good as that following a prime-boost regime with a 3-week dosing interval (89% at 15-21 days (2) compared to 95% from day 29 onwards with a prime/boost regime (3)) but they will want to know how long this level of protection after only one dose will last, and how any extended dosing interval will affect the response to a booster in terms both of efficacy and duration.
As a GP, I will struggle to answer their questions because of weaknesses in the quality of evidence presented by the JCVI, who state that “the second dose is still important to provide longer lasting protection and is expected to be as or more effective when delivered at an interval of 12 weeks from the first dose” (2).
Expected is the key word here. We must bear in mind that: (a) SARS-CoV-2 is a newly emerged pathogen – clinicians and researchers experienced in infectious diseases advise us to be humble and cautious in our assumptions about the behaviour of new pathogens; (b) the correlates of protection against infection, infectiousness, symptomatic or severe Covid-19 disease are not known, nor whether these might vary (say) by age (5); (c) neither the Pfizer BNT162b2 nor Moderna mRNA1273 vaccine trials that have been reported so far were designed to evaluate different dosing intervals (3,6); (d) mRNA-based vaccines are a new technology – even though there is a strong foundation of pre-clinical research using various mRNA platforms (7,8), BNT162b2 and mRNA1273 are the first such vaccines to have been approved for use against infectious disease in a broad section of the population.
The JCVI document reads, in part, like an Olympian pronouncement (2). This contrasts with the reasoning in reports that clinicians are accustomed to reading from NICE, whose technology appraisals and guidelines contain explicit acknowledgements of uncertainty and limits to evidence. Clinicians and the public understand the imperative to act despite imperfect evidence because of the rapidly evolving pandemic. However, a lack of transparency about some of the evidence behind current decision making does not sit well with earlier reassurances that no corners have been cut in the expedited development and deployment of Covid-19 vaccines.
So, what is the evidence for and against an extended prime-boost vaccine dosing interval against respiratory viruses in humans, and how might this be relevant to mRNA vaccines against SARS-CoV-2? How well might any such evidence about vaccine use in children translate to adults?
Key questions include the effects of an extended prime-boost vaccine dosing interval on:
1. Safety, immunogenicity, efficacy and duration of the immune response in humans?
2. The patterning of antibody binding and T cell specificity to different target epitopes, bearing in mind the potential for new variants of SARS-CoV-2 to emerge?
3. The direction of skewing of T-cell responses?
4. Coordination between different arms of the adaptive immune response, including mucosal immunity?
Does such evidence depend on the type of vaccine technology? Is there any evidence specifically for mRNA vaccines, besides the limited data in a report by Feldman et al that prolonging the dosing interval (in only 5 participants) for an mRNA vaccine against H7N9 influenza from 21 days to 6 months increased, or at least preserved, immunogenicity 3 weeks after the second dose, as judged by haemagglutination inhibition assay titres or microneutralization assay titres, respectively (9)?
References
1. https://www.gov.uk/government/news/statement-from-the-uk-chief-medical-o... (accessed 3 January 2021)
2. https://m.box.com/shared_item/https%3A%2F%2Fapp.box.com%2Fs%2Fiddfb4ppwk... (accessed 3 January 2021)
3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10. PMID: 33301246; PMCID: PMC7745181.
4. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based covid-19 vaccine candidates. N Engl J Med. 2020 Dec 17;383(25):2439-2450. doi: 10.1056/NEJMoa2027906. Epub 2020 Oct 14. PMID: 33053279; PMCID: PMC7583697.
5. Plotkin SA. Updates on immunologic correlates of vaccine-induced protection. Vaccine. 2020 Feb 24;38(9):2250-2257. doi: 10.1016/j.vaccine.2019.10.046. Epub 2019 Nov 22. PMID: 31767462.
6. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020 Dec 30. doi: 10.1056/NEJMoa2035389. Epub ahead of print. PMID: 33378609.
7. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics - developing a new class of drugs. Nat Rev Drug Discov. 2014 Oct;13(10):759-80. doi: 10.1038/nrd4278. Epub 2014 Sep 19. PMID: 25233993.
8. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018 Apr;17(4):261-279. doi: 10.1038/nrd.2017.243. Epub 2018 Jan 12. PMID: 29326426; PMCID: PMC5906799.
9. Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine. 2019 May 31;37(25):3326-3334. doi: 10.1016/j.vaccine.2019.04.074. Epub 2019 May 10. PMID: 31079849.
Competing interests:
I work as a GP in Yorkshire. I am a former member of the NICE technology appraisal committee A, which did not have responsibility for vaccines. I was briefly an employee of Pfizer in 1998 (2 months) and did not work on vaccines. Neither I nor any member of my family hold stock or shares in Pfizer or any other pharmaceutical company. I received the first dose of the Pfizer vaccine in December 2020.
Rapid Response:
Where is the evidence that extending the dosing interval for the Pfizer mRNA vaccine from 3 weeks to 12 weeks is effective and safe?
Dear Editor
The four Chief Medical Officers (CMOs) of the United Kingdom and the Deputy CMO for England wrote to the profession on 31 December 2020 to explain their rationale for the dosing schedule for the Oxford vaccine and the change to the dosing schedule for the Pfizer vaccine, to maximise the public health benefits of the vaccine roll-out this winter (1). They supported their arguments with a report from the Joint Committee on Vaccination and Immunisation (JCVI) Optimising the COVID-19 vaccination programme for maximum short-term impact, 31/12/20 (2).
Table 1, Annex A of the report tabulates vaccine efficacy (VE) for the Pfizer vaccine at 15-21 days, 22-28 days and 15-28 days after the first dose (2). The VE at 15-28 days (one week either side of the booster dose on day 22) is 91% (95%CI 74-97). The post-hoc analysis behind this estimate preserves randomisation, is based on apparent reasonable assumptions about time lags before a clinical response to vaccination and is supported by data-derived evidence for the separation of symptomatic Covid-19 incidence curves in the two trial arms (3). Such a high VE so early is reassuring, particularly as the lower bound of the 95% confidence interval for the Pfizer vaccine at 15-28 days is 74%. Although the booster on day 22 may have some effect before day 28, in line with a reported increase in 50% neutralizing antibody titre between days 21 and 28 (4), a VE of 89% (52-97) at 15-21 days is also reassuring (2).
The JCVI present a convincing argument that most of the benefit of the Pfizer vaccine occurs early and that we can anticipate a greater public health benefit in the short term if we accelerate recruitment by postponing the booster and vaccinating twice as many people with a single dose initially (2).
But what then? Patients will be reassured that initial protection with the first Pfizer vaccine dose alone is almost as good as that following a prime-boost regime with a 3-week dosing interval (89% at 15-21 days (2) compared to 95% from day 29 onwards with a prime/boost regime (3)) but they will want to know how long this level of protection after only one dose will last, and how any extended dosing interval will affect the response to a booster in terms both of efficacy and duration.
As a GP, I will struggle to answer their questions because of weaknesses in the quality of evidence presented by the JCVI, who state that “the second dose is still important to provide longer lasting protection and is expected to be as or more effective when delivered at an interval of 12 weeks from the first dose” (2).
Expected is the key word here. We must bear in mind that: (a) SARS-CoV-2 is a newly emerged pathogen – clinicians and researchers experienced in infectious diseases advise us to be humble and cautious in our assumptions about the behaviour of new pathogens; (b) the correlates of protection against infection, infectiousness, symptomatic or severe Covid-19 disease are not known, nor whether these might vary (say) by age (5); (c) neither the Pfizer BNT162b2 nor Moderna mRNA1273 vaccine trials that have been reported so far were designed to evaluate different dosing intervals (3,6); (d) mRNA-based vaccines are a new technology – even though there is a strong foundation of pre-clinical research using various mRNA platforms (7,8), BNT162b2 and mRNA1273 are the first such vaccines to have been approved for use against infectious disease in a broad section of the population.
The JCVI document reads, in part, like an Olympian pronouncement (2). This contrasts with the reasoning in reports that clinicians are accustomed to reading from NICE, whose technology appraisals and guidelines contain explicit acknowledgements of uncertainty and limits to evidence. Clinicians and the public understand the imperative to act despite imperfect evidence because of the rapidly evolving pandemic. However, a lack of transparency about some of the evidence behind current decision making does not sit well with earlier reassurances that no corners have been cut in the expedited development and deployment of Covid-19 vaccines.
So, what is the evidence for and against an extended prime-boost vaccine dosing interval against respiratory viruses in humans, and how might this be relevant to mRNA vaccines against SARS-CoV-2? How well might any such evidence about vaccine use in children translate to adults?
Key questions include the effects of an extended prime-boost vaccine dosing interval on:
1. Safety, immunogenicity, efficacy and duration of the immune response in humans?
2. The patterning of antibody binding and T cell specificity to different target epitopes, bearing in mind the potential for new variants of SARS-CoV-2 to emerge?
3. The direction of skewing of T-cell responses?
4. Coordination between different arms of the adaptive immune response, including mucosal immunity?
Does such evidence depend on the type of vaccine technology? Is there any evidence specifically for mRNA vaccines, besides the limited data in a report by Feldman et al that prolonging the dosing interval (in only 5 participants) for an mRNA vaccine against H7N9 influenza from 21 days to 6 months increased, or at least preserved, immunogenicity 3 weeks after the second dose, as judged by haemagglutination inhibition assay titres or microneutralization assay titres, respectively (9)?
References
1. https://www.gov.uk/government/news/statement-from-the-uk-chief-medical-o... (accessed 3 January 2021)
2. https://m.box.com/shared_item/https%3A%2F%2Fapp.box.com%2Fs%2Fiddfb4ppwk... (accessed 3 January 2021)
3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10. PMID: 33301246; PMCID: PMC7745181.
4. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based covid-19 vaccine candidates. N Engl J Med. 2020 Dec 17;383(25):2439-2450. doi: 10.1056/NEJMoa2027906. Epub 2020 Oct 14. PMID: 33053279; PMCID: PMC7583697.
5. Plotkin SA. Updates on immunologic correlates of vaccine-induced protection. Vaccine. 2020 Feb 24;38(9):2250-2257. doi: 10.1016/j.vaccine.2019.10.046. Epub 2019 Nov 22. PMID: 31767462.
6. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020 Dec 30. doi: 10.1056/NEJMoa2035389. Epub ahead of print. PMID: 33378609.
7. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics - developing a new class of drugs. Nat Rev Drug Discov. 2014 Oct;13(10):759-80. doi: 10.1038/nrd4278. Epub 2014 Sep 19. PMID: 25233993.
8. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018 Apr;17(4):261-279. doi: 10.1038/nrd.2017.243. Epub 2018 Jan 12. PMID: 29326426; PMCID: PMC5906799.
9. Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine. 2019 May 31;37(25):3326-3334. doi: 10.1016/j.vaccine.2019.04.074. Epub 2019 May 10. PMID: 31079849.
Competing interests: I work as a GP in Yorkshire. I am a former member of the NICE technology appraisal committee A, which did not have responsibility for vaccines. I was briefly an employee of Pfizer in 1998 (2 months) and did not work on vaccines. Neither I nor any member of my family hold stock or shares in Pfizer or any other pharmaceutical company. I received the first dose of the Pfizer vaccine in December 2020.