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Appendix 1
1. Prior COVID-19 infection
At least eight small studies have shown that those with previous COVID-19 disease produce a strong
antibody response after a single dose of vaccine.[1-6] This response is similar in magnitude to that
seen after two doses in those without prior COVID-19 disease. One of these studies also found that
the SARS-CoV-2 infection also led to increased numbers of double negative B memory cells, which
might be a “dysfunctional B cel  subset”.[1] One study has also shown that a single dose of Pfizer
vaccination after infection with “original strain” virus substantially enhances neutralising antibody
responses against variants including the Beta variant [7].Overal  it has been suggested that
vaccination following infection results in a broader and greater magnitude neutralising antibody
response than vaccination in SARS-CoV-2 naïve individuals.[8]
Prior infection may also increase the durability of immunity. A Spanish study comparing antibody
titres in previously infected and infection naïve healthcare workers found that at two months post-
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vaccination, the previously infected group had higher antibody titres.[9]

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2. Immunogenicity
2.1.
General
This vaccine is immunogenic. In 18-55 year olds, neutralising antibody levels were 3.8 times that in
convalescent plasma 1 week after the second dose and in 65-85 year olds 1.6 tim
Information  es, with all vaccine
recipients in both age groups producing detectable neutralising antibody titres.[10] Data from a
phase 3 trial in adolescents (12-15 years of age) showed a strong neutralising antibody response to
vaccination.[11]
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In a (non-peer reviewed) observational study, uniformly robust IgG responses across all vaccinees
were only seen after the second dose was administered.[12]
the
When comparing Pfizer vaccination with natural infection, a (non-peer reviewed) study found that
vaccination generated lower levels of original antigenic sin-like antibodies and higher levels of SARS-
CoV2 specific antibodies.[13] The implic
under  ations of the cellular response to Pfizer are under-
researched. However, a (non-peer reviewed) study monitoring cel ular responses to vaccination in
the 6-months after the second dose found CD4+ and CD8+ lymphocytes display features of
polyfunctionality and longevity.[14]
2.2.
Single-
Released  dose schedule
The neutralising antibody titres generated by one dose are significantly less than those generated
after two doses. Furthermore, in the interdose period during an extended interval, neutralising
antibody responses have been seen to wane fol owing a peak at around 4 weeks, however the T cell
response has been seen to persist. As with post two doses, there is variability seen in the magnitude
of the antibody response after the first dose, with it generally higher in healthy younger adults,
however there is limited data on whether the kinetics of the response are similar over the extended
intervals.[15-20]

Appendix 1
2.3.
Extended interval two-dose schedule
Studies have found that extended intervals between the first and second dose produce higher peak
spike-specific antibody responses (3.5-fold higher among 172 80+ participants with a 12-week
interval,[21]  and ~2-fold among 280 infection-naïve healthcare workers with a 6-14 week
interval[16]). However, longer intervals were associated with lower peak T-cel  responses when
compared to the 3-week interval (3.6 fold in the 80+ group,[21] and 1.59-fold among healthcare
workers[16]). Yet among the healthcare workers, the longer interval saw a greater proportion of the
T cell response comprised by CD4+ cells and was suggestive of a more developed memory cell
phenotype. There were no significant differences between the intervals for 223 previously infected
healthcare workers in this study.[16]  A Canadian (non-peer reviewed) study has also that found
while delaying the second-dose reduced spike-specific CD4+ T-cell responses (>2-fold reduction in
median T-cell frequency), anti-RBD binding titres were significantly elevated (3.3-fold increase).[22]
A UK (non-peer reviewed) study, in ages 50+, found that anti-S IgG titres were ~10x fold higher in
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those with a 65-84 day interval vs the regular 19-29 day interval.[23] Another UK study compared
immunogenicity in adults after they received standard or extended-interval schedules o
Act f the Pfizer
vaccine. They found that the extended interval was associated with higher neutralising antibody
levels and an enrichment of CD4+ T cells expressing IL2.[24]
Some evidence suggests that the longer schedule may have a limited effect on the duration of
immune response. A (non-peer reviewed) study of antibody responses fol owing the second dose of
Pfizer found that while shorter intervals were associated with a lower antibody response at day 21,
Information
however by day 42 they were similar to longer intervals. When analyses were limited to the <70 age
group, there was no difference between short and extended intervals.[25]
A Canadian (non-peer reviewed) study found that a 16-week interval generated a similar neutralising
antibody response to those who had been previously infec
Official ted and received one dose.[26]

the

under
Released

Appendix 1
3. References
1.
Mishra, P.K., et al. Vaccination boosts protective responses and counters SARS-CoV-2-induced
pathogenic memory B cel s. 14 April 2021; Available from:
https://www.medrxiv.org/content/10.1101/2021.04.11.21255153v1.
2.
Taubel, J., et al. Do post-COVID-19 patients need a second dose of vaccine? 13 April 2021;
Available from: https://www.medrxiv.org/content/10.1101/2021.04.09.21255200v1.
3.
Anichini, G., et al., SARS-CoV-2 Antibody Response in Persons with Past Natural Infection. N
Engl J Med, 2021.
4.
Konstantinidis, T., et al. Levels of produced antibodies after vaccination with mRNA vaccine;
effect of previous infection with SARS-CoV-2. 7 April 2021; Available from:
https://www.medrxiv.org/content/10.1101/2021.04.05.21254934v1.
5.
Vickers, M.A., et al., Exponential increase in neutralizing and spike specific antibodies
fol owing vaccination of COVID-19 convalescent plasma donors. Transfusion, 2021.
6.
Goel, R.R., et al., Distinct antibody and memory B cel  responses in SARS-CoV-2 naive and
recovered individuals fol owing mRNA vaccination. Sci Immunol, 2021. 6(58).  1982
7.
Reynolds, C.J., et al., Prior SARS-CoV-2 infection rescues B and T cel  responses to variants
after first vaccine dose. Science, 2021.
Act
8.
Crotty, S., Hybrid immunity. Science, 2021. 372(6549): p. 1392-1393.
9.
Ontañón, J., et al., Influence of past infection with SARS-CoV-2 on the response to the
BNT162b2 mRNA vaccine in health care workers: Kinetics and durability of the humoral
immune response. EBioMedicine, 2021. 73: p. 103656.
10.
Walsh, E.E., et al., Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine
Candidates. N Engl J Med, 2020.
11.
Pfizer. Pfizer-biontech announce positive topline results of pivotal covid-19 vaccine study in
adolescents. 31 March 2021; Available from: https://www.pfizer.com/ne
Information ws/press-
release/press-release-detail/pfizer-biontech-announce-positive-topline-results-pivotal.
12.
Viana, J.F., et al. Population homogeneity for the antibody response to COVID-19 Comirnaty
vaccine is only reached after the second dose. 24 March 2021; Available from:
https://www.medrxiv.org/content/10.1101/2021.03.19.21253680v1.
Official
13.
Anderson, E.M., et al., SARS-CoV-2 infections elicit higher levels of original antigenic sin
antibodies compared to SARS-CoV-2 mRNA vaccinations. 2021, Cold Spring Harbor
Laboratory.
the
14.
Guerrera, G., et al., The BNT162b2 mRNA vaccine induces polyfunctional T cel  responses
with features of longevity. 2021, Cold Spring Harbor Laboratory.
15.
Wei, J., et al., Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general
under
population of the United Kingdom. Nature Microbiology, 2021.
16.
Payne , R., et al., Sustained T cel  immunity, protection and boosting using extended dosing
intervals of BNT162b2 mRNA vaccine. 23rd July 2021.
17.
Shrotri, M., et al., Spike-antibody responses to ChAdOx1 and BNT162b2 vaccines by
demographic and clinical factors (Virus Watch study). 2021, Cold Spring Harbor Laboratory.
18.
Collier, D.A., et al., Age-related immune response heterogeneity to SARS-CoV-2 vaccine
BNT162b2. Nature
Released , 2021.
19.
Viana, J.F., et al., Population homogeneity for the antibody response to COVID-19 BNT162b2
/ Comirnaty vaccine is only reached after the second dose, across all adult age ranges. 2021,
Cold Spring Harbor Laboratory.
20.
Herzberg, J., et al., SARS-CoV-2-antibody response in health care workers after vaccination or
natural infection in a longitudinal observational study. 2021, Cold Spring Harbor Laboratory.
21.
Parry, H., et al. Extended interval BNT162b2 vaccination enhances peak antibody generation
in older people. 17 May 2021; Available from:
https://www.medrxiv.org/content/10.1101/2021.05.15.21257017v1.ful -text.
22.
Hall, V., et al., Delayed interval BNT162b2 mRNA COVID-19 vaccination provides robust
immunity. 2021, Research Square Platform LLC.

Appendix 1
23.
Amirthalingam, G., et al., Higher serological responses and increased vaccine effectiveness
demonstrate the value of extended vaccine schedules in combatting COVID-19 in England.
28th July 2021, Cold Spring Harbor Laboratory.
24.
Payne, R.P., et al., Immunogenicity of standard and extended dosing intervals of BNT162b2
mRNA vaccine. Cell, 2021. 0(0).
25.
Wei, J., et al., SARS-CoV-2 anti-spike IgG antibody responses after second dose of ChAdOx1 or
BNT162b2 in the UK general population. 2021, Cold Spring Harbor Laboratory.
26.
Tauzin, A., et al., Strong humoral immune responses against SARS-CoV-2 Spike after
BNT162b2 mRNA vaccination with a sixteen-week interval between doses. 21st September
2021, Cold Spring Harbor Laboratory.

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