Safety and immunogenicity report from the com cov study

1 Safety and immunogenicity report from the Com-COV study – A single-blind randomised non-2 inferiority trial comparing heterologous and homologous prime-boost schedules with an 3 adeno

1 Safety and immunogenicity report from the Com-COV study – A single-blind randomised

non-2 inferiority trial comparing heterologous and homologous prime-boost schedules with an

3 adenoviral vectored and mRNA COVID-19 vaccine.

4 Xinxue Liu*1, PhD; Robert H Shaw*1,2, MRCP; Arabella SV Stuart*1,2, MSc; Melanie Greenland1, MSc;

5 Tanya Dinesh1, MSci; Samuel Provstgaard-Morys1, BSc; Elizabeth A Clutterbuck, PhD1; Maheshi N

6 Ramasamy1,2, DPhil; Parvinder K Aley1, PhD; Yama F Mujadidi1, MSc; Fei Long1, MSc; Emma L

7 Plested1, Hannah Robinson1, RN; Nisha Singh1, DPhil; Laura L Walker1; Rachel White1, RN; Nick J

8 Andrews3, PhD; J Claire Cameron4, FFPH; Andrea M Collins5, PhD; Daniella M Ferreira5, PhD; Helen

9 Hill5, PhD; Christopher A Green6, DPhil; Bassam Hallis3, PhD; Paul T Heath7, FRCPCH; Saul N Faust8,

10 PhD; Adam Finn9,PhD; Teresa Lambe10, PhD; Rajeka Lazarus11, DPhil; Vincenzo Libri12, MD; Mary

11 Ramsay3, PhD; Robert C Read8 PhD; David PJ Turner13, PhD; Paul J Turner, PhD14; Jonathan S

Nguyen-12 Van-Tam15, DM; Matthew D Snape1,16^, MD; and the Com-COV Study Group†

13

14 1 Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK

15 2 Oxford University Hospitals NHS Foundation Trust, Oxford, UK

16 3 Public Health England

17 4 Public Health Scotland

18 5 Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool, L3

20 6 NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS

21 Foundation Trust, Birmingham B15 2TH, UK

22 7 The Vaccine Institute, St George's University of London, Cranmer Terrace, London SW17 0RE,

24 8 NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University

25 Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK; Faculty of Medicine

26 and Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK

27 9 Schools of Population Health Sciences and Cellular and Molecular Medicine, University of

28 Bristol, Bristol, UK

29 10 Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive,

30 Headington, Oxford OX3 7DQ, UK

31 11 North Bristol NHS Trust, Southmead Road, Bristol BS10 5NB, UK

32 12 NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University

33 Preprint not peer reviewedCollege London Hospitals NHS Foundation Trust, London W1T 7HA, UK

35 13 University of Nottingham, Nottingham, NG7 2RD, UK; Nottingham University Hospitals NHS

36 Trust, Nottingham, NG7 2UH, UK

37 14 National Heart & Lung Institute, Imperial College London, Dovehouse St, London SW3 6LY, UK

38 15 Division of Epidemiology and Public Health, University of Nottingham School of Medicine,

39 Nottingham, NG7 2UH, UK

40 16 Oxford NIHR – Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust,

41 Oxford, OX3 9DU, UK

42 *Contributed equally

43 ^ Corresponding author - Matthew D Snape, Oxford Vaccine Group, Department of Paediatrics,

44 University of Oxford, Oxford OX3 9DU, UK, matthew.snape@paediatrics.ox.ac.uk, Phone 01865

45 611400

46 †Com-COV Study Group authorship - appendix

Preprint not peer reviewed

47 Abstract

48 Background

49 Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19

50 immunisation, however we have previously reported that heterologous schedules incorporating an

51 adenoviral-vectored vaccine (ChAd, Vaxzevria, Astrazeneca) and an mRNA vaccine (BNT, Comirnaty,

52 Pfizer) at a 4-week interval are more reactogenic than homologous schedules Here we report the

53 immunogenicity of these schedules

54 Methods

55 Com-COV (ISRCTN: 69254139, EudraCT: 2020-005085-33) is a participant-blind, non-inferiority trial

56 evaluating vaccine reactogenicity and immunogenicity Adults ≥ 50 years, including those with

well-57 controlled comorbidities, were randomised across eight groups to receive ChAd/ChAd, ChAd/BNT,

58 BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals

59 The primary endpoint is geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG levels (ELISA)

60 at one-month post boost between heterologous and homologous schedules given the same prime

61 vaccine We tested non-inferiority of GMR using a margin of 0.63 The primary analysis was on a

per-62 protocol population, who were seronegative at baseline Safety analyses were performed amongst

63 participants receiving at least one dose of study vaccines

64 Findings

65 In February 2021, 830 participants were enrolled and randomised, including 463 with a 28-day

prime-66 boost interval whose results are reported in this paper Participant mean age was 57.8 years, 45.8%

67 were female, and 25.3% from ethnic minorities

68 The geometric mean concentration (GMC) of day 28 post-boost SARS-CoV-2 anti-spike IgG in

69 ChAd/BNT recipients (12,906 ELU/ml) was non-inferior to that in ChAd/ChAd recipients (1,392 ELU/ml)

70 with a geometric mean ratio (GMR) of 9.2 (one-sided 97.5% CI: 7.5, ) In participants primed with

71 BNT, we failed to show non-inferiority of the heterologous schedule (BNT/ChAd, GMC 7,133 ELU/ml)

72 against the homologous schedule (BNT/BNT, GMC 14,080 ELU/ml) with a GMR of 0.51 (one-sided

73 97.5% CI: 0.43, ) Geometric mean of T cell response at 28 days post boost in the ChAd/BNT group

74 was 185 SFC/106 PBMCs (spot forming cells/106 peripheral blood mononuclear cells) compared to 50,

75 80 and 99 SFC/106 PBMCs for ChAd/ChAd, BNT/BNT, and BNT/ChAd, respectively.There were four

76 serious adverse events across all groups, none of which were considered related to immunisation

78 Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the GMCs of both heterologous

79 schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy

80 against COVID-19 disease and hospitalisation These data support flexibility in the use of heterologous

81 prime-boost vaccination using ChAd and BNT COVID-19 vaccines

82 Funding

83 Funded by the UK Vaccine Task Force (VTF) and National Institute for Health Research (NIHR)

Preprint not peer reviewed

84 Introduction

85 COVID-19 has severely impacted the world in terms of health, society and economy.(1) Immunity

86 through vaccination is fundamental to reducing the burden of disease, the emergence from current

87 public health measures and the subsequent economic recovery Multiple vaccines with proven

88 effectiveness are being deployed globally, including the mRNA vaccine Comirnaty (BNT, Pfizer) and

89 the adenoviral vectored vaccine Vaxzevria (ChAd, AstraZeneca), both of which are approved as

two-90 dose homologous schedules in the UK and elsewhere.(2)

91 As of June 2021, around 2 billion COVID-19 vaccines were administered worldwide,(3) but many more

92 people remain unimmunised Heterologous vaccine schedules may ease logistical problems inherent

93 in some national and international vaccine programmes This could prove of particular importance in

94 low- and middle-income countries(4) as well as in countries which have adopted age-specific

95 restrictions for the use of ChAd.(5–7)

96 While the Sputnik V vaccine programme, which deploys a heterologous prime-boost schedule using

97 Ad26 and Ad5 vectored COVID-19 vaccines, induces a robust humoral and cellular response and has

98 shown 91.6% efficacy against symptomatic disease,(8,9) there are currently no efficacy data using

99 heterologous schedules incorporating COVID-19 vaccines across different platforms Nevertheless,

100 pre-clinical studies support evaluation of this approach,(10,11) and a randomised study in Spain

101 suggested that there is an increase in binding and neutralising antibody after boosting ChAd primed

102 participants with BNT, compared with not having a boost dose.(12) Additionally, early results from an

103 observational study in Germany show that humoral responses are similar in the cohort receiving

104 BNT/BNT at a 3-week interval to those receiving ChAd/BNT at 10-week interval, with cellular responses

105 appearing to be higher in the ChAd/BNT cohort.(13)

106 Robust data on the safety and immunogenicity of heterologous vaccine schedules will help inform the

107 use of these schedules in individuals who develop a contraindication to a specific vaccine after their

108 first dose, and for vaccine programmes looking to mitigate vaccine supply chain disruption or changes

109 in guidance for vaccine usage In addition, there remains the possibility that mixed schedules may

110 induce an enhanced or more durable humoral and/or cellular immune response compared to licensed

111 schedules, and may do so against a greater range of SARS-CoV-2 variants

112 Accordingly, we have undertaken a randomised controlled trial to determine whether the immune

113 responses to heterologous schedules deploying ChAd and BNT are non-inferior to their equivalent

114 homologous schedules

115 Preprint not peer reviewed

116 Methods

118 Com-COV is a participant-blinded, randomised, phase II, UK multi-centre, non-inferiority study

119 investigating the safety, reactogenicity and immunogenicity of heterologous prime-boost COVID-19

120 vaccine schedules (See supplementary or https://comcovstudy.org.uk/ for full protocol) Four

121 permutations of prime-boost schedules using the ChAd and BNT vaccines are compared, at two

122 different prime-boost intervals (28 and 84 days) to reflect both ‘short’ and ‘long’ interval approaches

123 to immunisation The majority of participants were enrolled into the ‘General cohort’ in which

124 participants could be randomised to receive the four vaccine schedules at either a 28 or 84 day

125 interval, while a subset (N=100, selected on the basis of site capacity and participant availability) were

126 enrolled into an immunology cohort that only randomised individuals to vaccine schedules with a 28

127 day interval and had four additional blood tests

128 Here we report data from all participants randomised to vaccine schedules with a prime/boost interval

129 of 28 days

131 COVID-19 vaccine-nạve adults aged 50 years and over, with no or well-controlled mild-moderate

132 comorbidities were eligible for recruitment Key exclusion criteria were previous laboratory confirmed

133 SARS-CoV-2 infection, history of anaphylaxis, history of allergy to a vaccine ingredient, pregnancy,

134 breastfeeding or intent to conceive, and current use of anticoagulants Full details of the inclusion and

135 exclusion criteria can be found in the protocol (supplementary file)

137 Participants who met the inclusion and exclusion criteria via the online screening and/or the

138 telephone screening were invited to the baseline visits (D0), where randomisation occurred for those

139 passing the final eligibility assessment and providing informed consent

140 Two COVID-19 vaccines were used in this study ChAd is a replication-deficient chimpanzee adenovirus

141 vectored vaccine, expressing the SARS-CoV-2 spike surface glycoprotein with a leading tissue

142 plasminogen activator signal sequence Administration is via 0.5ml intramuscular (IM) injection into

143 the upper arm BNT is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine encoding

144 trimerised SARS-CoV-2 spike glycoprotein Administration is via a 0.3ml IM injection into the upper

145 arm

Preprint not peer reviewed

146 Vaccines were administered by appropriately trained trial staff at trial sites Participants were

147 observed for at least 15 minutes after vaccination During the D0 visit, participants were given an oral

148 thermometer, tape measure and diary card (electronic or paper) to record solicited, unsolicited, and

149 medically attended adverse events (AEs) with instructions The study sites’ physicians reviewed the

150 diary card regularly to record AEs, adverse events of special interest (AESIs), and serious adverse

151 events (SAEs) The time-points for subsequent visits for immunogenicity blood sampling are shown in

152 the supplementary protocol During the study visits, AEs, AESIs and SAEs that had not been recorded

153 in the diary card were also collected

154 Participants testing positive for SARS-CoV-2 in the community were invited for an additional visit for

155 clinical assessment, collection of blood samples and throat swab, and completion of a COVID-19

156 symptom diary

158 Computer-generated randomisation lists were prepared by the study statistician Participants were

159 block randomised (block size four) 1:1:1:1 within the immunology cohort to ChAd/ChAd, ChAd/BNT,

160 BNT/BNT and BNT/ChAd schedules (boost interval of 28 days) General Cohort participants were block

161 randomised (block size eight) 1:1:1:1:1:1:1:1 to ChAd/ChAd, ChAd/BNT, BNT/BNT and BNT/ChAd

162 schedules at boosting intervals of both 28 and 84 days Randomisation was stratified by study site

163 Clinical research nurses who were not involved in safety endpoint evaluation performed the

164 randomisation using REDCapTM (the electronic data capture system) and prepared and administered

165 vaccine

166 Participants and laboratory staff processing the immunogenicity endpoints were blinded to vaccines

167 received, but not to prime-boost interval Participant blinding to vaccines was maintained by

168 concealing randomisation pages, preparing vaccines out of sight and applying masking tape to vaccine

169 syringes to conceal dose volume and appearance The clinical team assessing the safety endpoints

170 were not blinded

172 The primary outcome is serum SARS-CoV-2 anti-spike IgG concentration at 28 days post boost for

173 those with a prime-boost interval of 28 days in participants who were seronegative for COVID infection

174 at baseline

175 Secondary outcomes include safety and reactogenicity as measured by solicited local and systemic

176 events for 7 days after immunisation (reported previously for the 28-day prime-boost interval

177 groups),(14) unsolicited AEs for 28 days after immunisation and medically attended AEs for 3 months Preprint not peer reviewed

178 after immunisation Blood biochemistry and haematology assessments were measured at baseline

179 (day 0), on day of boost and 28 days post-boost, with an additional day 7 post-boost time-point (D35)

180 for the immunology cohort only AESIs (listed in protocol as a supplementary file) and SAEs were

181 collected throughout the study

182 Immunological secondary outcomes include SARS-CoV-2 anti-spike binding IgG concentration, cellular

183 responses (measured by IFN-gamma ELISpot) in peripheral blood, and pseudotype virus neutralisation

184 titres at D0, D28 and D56 The immunology cohort had additional visits at D7, D14, D35 and D42 to

185 explore the kinetics of the immune responses further

186 Laboratory methods

187 Sera were analysed at Nexelis, (Laval, Canada) to determine SARS-CoV-2 anti-spike IgG concentrations

188 by ELISA (reported as ELISA Laboratory Unit (ELU)/ml) and the 50% Neutralising Antibody Titre (NT50)

189 for SARS-CoV-2 pseudotype virus neutralisation assay (PNA), using a vesicular stomatitis virus

190 backbone adapted to bear the 2019-nCOV SARS-CoV-2 spike protein(15) Sera from day 0 were

191 analysed at Porton Down, Public Health England, by ECLIA (Cobas platform, Roche Diagnostics) to

192 determine anti-SARS-CoV-2 nucleocapsid IgG status (reported as negative if below a cut off index of

193 1.0) NT50 for live SARS-CoV-2 virus (Victoria/01/2020) was determined by microneutralisation assay

194 (MNA) also at Porton Down, on day 0 and 56 samples in the AZ-primed groups only.(15)

Interferon-195 gamma secreting T-cells specific to whole spike protein epitopes designed based on the Wuhan-Hu-1

196 sequence (YP_009724390.1) were detected using a modified T-SPOT-Discovery test performed at

197 Oxford Immunotec (Abingdon, UK) within 32 hours of venepuncture, using the addition of T-Cell Xtend

198 reagent to extend PBMC survival.(16) T cell frequencies were reported as spot forming cells (SFC) per

199 250,000 PBMCs with a lower limit of detection of one in 250,000 PBMCs, and these results multiplied

200 by four to express frequencies per 106 PBMCs

202 The primary analysis of SARS-CoV-2 anti-spike IgG was carried out in participants boosted at D28 on a

203 per-protocol basis The analysis population was participants who were seronegative for COVID at

204 baseline (defined by anti-nucleocapsid IgG negativity at Day 0 and no confirmed SARS-CoV-2 infection

205 within 14 days post prime vaccination), whose primary endpoint datawere available and who had no

206 protocol deviations The geometric mean ratio (GMR) was calculated as the antilogarithm of the

207 difference between the mean of the log10 transformed SARS-CoV-2 anti-spike IgG in the heterologous

208 arm and that in the homologous arm (as the reference), after adjusting for study site and cohort

209 (immunology/general) as randomisation design variables in the linear regression model The GMRs

210 were reported separately for participants primed with ChAd and those with BNT with a one-sided Preprint not peer reviewed

211 97.5% confidence interval The criteria for non-inferiority of heterologous boost compared to the

212 homologous boost was for the lower limit of the one-sided 97.5% CI of the GMR to lie above 0.63; this

213 was chosen on a pragmatic basis to approach the WHO criterion of 0.67 for licencing new vaccines

214 when using GMR as the primary endpoint, while still allowing rapid study delivery.(17)

215 According to recommended practice for non-inferiority trials,(18) we also present the two-sided 95%

216 CI of the adjusted GMRs among the modified intent-to-treat (mITT) population by including

217 participants with protocol deviations as secondary analyses The heterologous arm was considered

218 superior to the homologous arm if the lower limit of the two-sided 95% CI lay above one, and the

219 homologous boost arm superior to the heterologous boost arm if the upper limit of the two-sided 95%

220 CI lay below one As an exploratory analysis, subgroup analyses were conducted stratified by age

(50-221 59, and 60+), sex (male and female) and baseline comorbidity (presence/absence of cardiovascular

222 disease, respiratory disease or diabetes)

223 The geometric means of secondary immunological outcomes were reported in the mITT population

224 The proportions of participants with responses higher than the lower limit of detection (LLOD) or

225 lower limit of quantification (LLOQ) were calculated by vaccine schedule, with 95% CIs calculated by

226 the binomial exact method for each secondary immunological outcome, and compared between

227 heterologous and homologous arms using Fisher's exact test Censored data reported as below the

228 LLOD/LLOQ were imputed with a value equal to half of the threshold before transformation

Between-229 schedule comparisons of immunological outcomes were evaluated by linear regression models

230 adjusting for study site and cohort as secondary analyses Correlations between different

231 immunological outcomes were evaluated by Pearson correlation coefficients

232 Participants who received at least one dose of study vaccines were included in the safety analysis The

233 proportion of participants with at least one safety event was reported by vaccine schedule Fisher's

234 exact test was used to compare the difference between schedules

235 The sample size calculation was done assuming the standard deviation (SD) of the primary endpoint

236 to be 0.4 (log10) and the true GMR to be one The study needed to recruit 115 participants per arm to

237 achieve 90% power at a one-sided 2.5% significance level, after adjusting for an attrition rate of 25%

238 due to baseline SARS-CoV-2 seropositivity or loss to follow-up

239 All the statistical analyses were carried out using R version 3.6.2 (2019-12-12)

241 The trial was reviewed and approved by the South-Central Berkshire Research Ethics Committee

242 (21/SC/0022), the University of Oxford, and the Medicines and Healthcare Products Regulatory Agency Preprint not peer reviewed

243 (MHRA) An independent data safety monitoring board (DSMB) reviewed safety data, and local

trial-244 site physicians provided oversight of all adverse events in real-time The trial is registered at

245 www.isrctn.com as ISRCTN: 69254139

246 Results

247 Between 11th February 2021 and 26th February 2021, 978 participants were screened at eight study

248 sites across England, among whom 830 were enrolled and randomised into the study 463 participants

249 were randomised to the four arms with a 28-day prime-boost interval reported here including 100

250 participants enrolled into the immunology cohort The mean age of the participants was 57.8 years

251 (SD 4.7) with 45.8% female participants and 25.3% from ethnic minorities Baseline characteristics

252 were well balanced across the four arms in both the general and immunology cohorts (Table 1) At

253 baseline, 20 (4.3%) participants were positive for anti-nucleocapsid IgG (cut-off index ≥1.0), evenly

254 distributed across groups The numbers of participants included in the modified intent-to-treat and

255 per-protocol analyses were 432 and 426, respectively (Figure 1)

256 Immune responses at 28 days post boost vaccination: Primary outcome and key secondary

258 Among participants primed with ChAd, the GMCs of SARS-CoV-2 anti-spike IgG at 28 days post boost

259 vaccination was 1,392 ELU/ml (95%CI: 1,188-1,630) and 12,906 ELU/ml (95%CI: 11,404-14,604) in

260 the homologous arm (ChAd/ChAd) and heterologous arm (ChAd/BNT), respectively, with a GMR of 9.2

261 (one-sided 97.5% CI: 7.5, ) between heterologous and homologous arms in the per-protocol analysis

262 (Table 2) Similar GMCs were observed in the modified ITT analysis with a GMR of 9.3 (two-sided 95%

263 CI: 7.7-11) The GMR of PNA NT50 (secondary outcome) between heterologous and homologous arms

264 was 8.5 (two-sided 95% CI: 6.5, 11) in the modified ITT analysis These results indicate that the

265 ChAd/BNT schedule was not only non-inferior, but statistically superior to ChAd/ChAd schedule for

266 both the SARS-CoV-2 anti-spike IgG and PNA NT50 The secondary outcome of cellular responses by

267 T-cell ELISpot revealed 50 SFC/106 PBMCs (39-63) for ChAd/ChAd and 185 SFC/106 PBMCs (152-224)

268 with a GMR of 3.8 (2.8-5.1) (Table 2)

269 In the two schedules with BNT as the prime vaccine, the GMCs of SARS-CoV-2 anti-spike IgG at 28 days

270 post boost vaccination were 14,080 ELU/ml (95%CI: 12,491-15,871) and 7,133 ELU/ml (95%CI:

6,415-271 7,932) for the homologous and heterologous arms in the protocol analysis The GMR in the

per-272 protocol analysis was 0.51 (one-sided 97.5% CI: 0.43, ) The study therefore failed to show

non-273 inferiority of the heterologous arm (BNT/ChAd) to its corresponding homologous arm (BNT/BNT) In

274 addition, BNT/ChAd was statistically inferior for both SARS-CoV-2 anti-spike IgG (p<0.0001) and PNA Preprint not peer reviewed

276 higher in the heterologous arm compared with the homologous arm (99 vs 80 SFC/106 PBMCs), though

277 did not reach a level of statistical significance (GMR: 1.2, two-sided 95% CI: 0.88-1.7)

278 Similar patterns of GMRs were seen in all subgroup analyses with SARS-CoV-2 anti-spike IgG and PNA

279 NT50 consistently higher in the ChAd/BNT compared with ChAd/ChAd and BNT/BNT higher than

280 BNT/ChAd (Figure 2) Strong correlations were seen between SARS-CoV-2 anti-spike IgG and PNA NT50

281 at 28 days post boost in all vaccine schedules (Pearson correlation coefficients of 0.6-0.7), while the

282 correlations between humoral responses and cellular response were weak (Pearson correlation

283 coefficients <0.4) (Figure 3)

284 Additional secondary outcomes

285 Immunology cohort: Humoral & cellular immune responses at 7 and 14 days post boost

287 Across all four schedules an increase in SARS-CoV-2 anti-spike IgG was seen from day 28 to day 35 (day

288 7 post boost), contrasting with a lack of response at day 7 post prime, suggesting that both vaccines

289 induced immunological priming that was augmented by either homologous or heterologous boost

290 (Figure 4 and Appendix Figure 1) No further increase in SARS-CoV-2 anti-spike IgG was seen at day 28

291 post boost, suggesting the peak response post-boost is likely to be earlier than 28 days For all

292 schedules except ChAd/ChAd, peak T cell response was observed at 14 days post boost; no further

293 increase was seen in ChAd/ChAd post boost (Appendix Figure 1)

294 Humoral & cellular immune responses: Post-prime vaccination

295 In participants primed with ChAd and BNT, the SARS-CoV-2 anti-spike IgG GMCs were 129 (95% CI:

80-296 206) and 843 (95% CI: 629-1130) ELU/ml at 14 days post prime (p<0.0001), and 555 (95% CI: 458-673)

297 and 1,597 (1,399-1,822) ELU/ml at 28 days post prime (p<0.0001), respectively

298 In contrast, ChAd induced significantly higher cellular responses at 14 days (p<0.0001) and 28 days

299 (p<0.0001) post prime vaccination compared with BNT: Geometric mean at 14 days was 160 (95% CI:

300 100-256) vs 35 SFC/106 PBMCs (95%CI: 26-47), and at 28 days was 54 (95% CI: 44-65) vs 16 SFC/106

301 PBMCs (95%CI: 14-18), respectively

302 Humoral & cellular immune responses: Cross-schedule comparisons

303 When BNT was given as the boost vaccine, similar levels of SARS-CoV-2 anti-spike IgG (p=0.43) and

304 PNA NT50 (p=0.40) at 28 days post-boost were observed among participants primed with ChAd

305 (ChAd/BNT) and BNT (BNT/BNT) Participants boosted with ChAd following BNT prime (BNT/ChAd)

306 had significantly higher SARS-CoV-2 anti-spike IgG (p<0.0001) and PNA NT50 (p<0.0001) than those

307 primed with ChAd (ChAd/ChAd) Homologous BNT/BNT immunisation generated higher binding Preprint not peer reviewed

308 antibodies at day 7 (p<0.0001) and day 28 (p<0.0001) post boost compared with ChAd/ChAd, with a

309 difference also observed in PNA at day 28 post boost (p<0.0001)

310 In contrast to the lack of further response following a homologous second dose of ChAd (Figure 4,

311 Appendix Figure 1), a significant increase in cellular response was seen after a homologous boost with

312 BNT, such that those receiving BNT/BNT had significantly higher number of SARS-CoV-2 specific T cells

313 per 106 PBMCs than ChAd/ChAd (p=0.0045) at 28 days post boost with a four week interval (Figure 4)

315 The results of the solicited adverse events in the week following immunisation have been reported

316 previously.(14) In summary, we observed an increase in systemic reactogenicity after boost in

317 participants receiving heterologous schedules in comparison to homologous schedules with the same

318 prime vaccine In participants randomised to 28-day interval groups there were 316 adverse events

319 from 178 participants up to 28 days following boost immunisation (Supplementary Table 1) No

320 significant difference was observed between the vaccine schedules (p=0.89) Adverse events of Grade

321 ≥3 are described in Supplementary Table 2

322 Amongst all participants up to 6th Jun 2021 (date of data-lock) there were seven AESIs, of which four

323 were COVID-19 diagnoses (Supplementary Tables 3 & 4) The non-COVID-19 AESIs were not

324 considered related to immunisation Four participants across all groups developed COVID-19 Three

325 were within 7 days of prime immunisation, one was 54 days later, and had not received their planned

326 28 day boost due to travel (Supplementary Table 4)

327 There were four SAEs across all groups in the study up to the data lock, and none was considered

328 related to immunisation (Supplementary table 5)

329

Preprint not peer reviewed

330 Discussion

331 We present here, for the first time in a randomised controlled clinical trial, the immunogenicity of

332 heterologous and homologous ChAd and BNT vaccine schedules with a 28-day prime-boost interval

333 The findings demonstrate that all the schedules studied induced concentrations of SARS-CoV-2

anti-334 spike IgG concentrations at least as high as those induced after a licensed ChAd/ChAd schedule, which

335 is effective in preventing symptomatic COVID-19 when administered at a 4-12 week prime-boost

336 interval.(19) Nevertheless, it is notable that the BNT containing schedules were more immunogenic

337 than the homologous ChAd/ChAd schedule, and none of the heterologous schedules generated

338 binding or pseudotype virus neutralising antibodies above those induced by BNT/BNT immunisation

339 Cellular immune responses in the BNT vaccine containing schedules were likewise all at least as high

340 as ChAd/ChAd group with BNT/ChAd showing the greatest expansion of vaccine-antigen responsive

T-341 cells in the peripheral circulation at 28 days post boost

342 Although the 28-day homologous ChAd/ChAd was the least immunogenic of the four schedules in our

343 trial, data from a phase 3 randomised clinical trial showed this regimen to be 76% efficacious against

344 symptomatic disease, and 100% against severe disease.(20) Additionally, when deployed in an 8 to 12

345 week schedule, ChAd/ChAd has been shown to be 86% and 92% effective against hospitalisation due

346 to the Alpha (B.1.1.7) and Delta (B.1.617.2) variants, respectively.(21–24) Given the established

347 associations between humoral responses and vaccine efficacy,(19) our findings indicate the two

348 heterologous schedules in this trial are also likely to be highly effective, and could be considered, in

349 some circumstances, for national vaccine programmes

350 To the best of our knowledge, the current study is the first randomised controlled trial to report

351 immunogenicity of the BNT/ChAd heterologous schedule Our results for the ChAd/BNT schedule build

352 on preliminary data from a Spanish randomised trial in which 18-60 year olds received a dose of BNT

353 two to three months after priming with ChAd and demonstrated a 37-fold increase in SARS-CoV-2

anti-354 spike IgG at 14 days post-boost, higher than the 22-fold and 19-fold rises at 7 days and 28 days post

355 boost in this study.(12) Potential explanations for these differences include the longer prime-boost

356 interval, the different sampling time-points and a younger population in the Spanish study.(12) Fold

357 rises in the cellular response were, however, similar (4-fold vs 3.5-fold) Early results from a

358 prospective cohort study in Germany, which compared healthcare workers immunised with BNT/BNT

359 at a 3-week interval or ChAd/BNT at an 8-12 week interval, showed similar concentrations of binding

360 antibody at 3 weeks post-boost and higher cellular responses in the ChAd/BNT recipients.(25) Another

361 German cohort study of 26 participants aged 25-46 years receiving a ChAd/BNT schedule with an

8-362 week prime-boost interval also reported a robust humoral immune response, with a suggestion of Preprint not peer reviewed

363 better retention of neutralising activity against Beta and Delta variants than that observed in a

non-364 randomised cohort receiving BNT/BNT.(26)

365 Together with the evidence that the T cell ELISpot readouts are similar between schedules, the

366 immunological data presented here provide reassurance that ChAd/BNT and BNT/ChAd are

367 acceptable options However, in contrast with recent non-randomised and non-blinded studies, we

368 did observe increased reactogenicity in the 28-day ChAd/BNT schedule (14), compared with

369 ChAd/ChAd This discrepancy may be due to the variation in the prime-boost interval, and the

370 forthcoming data from the 84-day prime-boost interval participants in this trial will help to delineate

371 this difference Although these mild-moderate symptoms were transient, this does need to be taken

372 into consideration when deploying this schedule, especially in those younger than the participants

373 enrolled in this study, given the reported trend towards increased reactogenicity with decreasing

374 age.(27,28) Additional considerations for deployment of mixed schedules include potential logistical

375 challenges within the healthcare infrastructure as well as the complex public communications

376 surrounding this

377 Numerous other randomised heterologous prime/boost COVID-19 vaccine studies are now underway

378 or planned,(29) including Com-COV2, which incorporates vaccines manufactured by Moderna and

379 Novavax.(30) Crucially, several of these studies include vaccines manufactured by CanSinoBIO,

380 Gamaleya Research Institute and Sinovac that are extensively used in low- and middle-income

381 countries, which are potentially more likely to rely on mixed schedules These data on heterologous

382 vaccination will also inform ‘3rd dose’ booster immunisation programmes, currently being considered

383 in preparation for the Northern Hemisphere 2021/2022 winter(31) and being studied in the ongoing

384 ‘Cov-Boost’ study.(32)

385 There are a number of limitations of this study Firstly, as an immunogenicity and reactogenicity study

386 the sample size is not adequate to assess vaccine schedule efficacy Although there is evidence that

387 both binding and neutralising antibodies correlate well with protection against symptomatic

388 disease,(19,33,34) it is less clear to what extent variations in these measures above a certain,

389 unknown, threshold impact on protection against severe disease Similarly, we are unable, at this

390 point, to determine whether higher antibody concentrations measured at 28 days post boost

391 immunisation will result in a more sustained elevation of vaccine-induced antibodies, and this will be

392 evaluated at ongoing study visits up to one-year post enrolment An additional limitation is the

393 generalisability of these results to a younger population given the age (50 – 70 years old) of

394 participants in this trial Previous RCTs on homologous schedules of viral vector and mRNA vaccines

395 reported similar post boost immunogenicity between younger (18-55 years) and older (>55 years) Preprint not peer reviewed

396 adults,(27,35,36) and higher reactogenicity in younger cohorts, (27,35,36) and there is no reason to

397 expect this would be different for the heterologous schedules but this has not been extensively

398 demonstrated Lastly, the data presented here were from schedules with a 28-day prime-boost

399 interval, whereas the WHO recommended interval for ChAd/ChAd is 8-12 weeks.(37) There is

400 evidence that a longer prime-boost interval results in a higher post-boost SARS-CoV-2 anti-spike IgG

401 response for ChAd/ChAd,(19) and for BNT/BNT (38) but it is unknown how lengthening the

prime-402 boost interval will affect the heterologous schedules in this study This question will be addressed

403 when the immunogenicity data for the schedules including boosting at 84 days become available

404 In conclusion, our study confirms the heterologous and homologous schedules of ChAd and BNT can

405 induce robust immune responses with a 4-week prime boost interval These results argue for allowing

406 for flexibility in deploying mRNA and viral vectored vaccines, subject to supply and logistical

407 considerations, and emphasise the importance of obtaining information on other mixed schedules

408 with different prime boost intervals, especially using vaccines being deployed in low- and

middle-409 income countries

410

Preprint not peer reviewed

411 Research in context

412 Evidence before this study

413 National regulatory authorities have granted emergency use authorizations for more than 15 vaccines,

414 among which six vaccines have been approved for emergency use by the World Health

415 Organisation.(2) Although >2 billion COVID-19 vaccines have been administered as of June 2021,(3)

416 only approximately 20% of the global population has received at least one dose of COVID-19 vaccine,

417 with less than 1% of the population in low-income countries having received a vaccine dose.(39)

418 Heterologous COVID-19 vaccine schedules have the potential to accelerate vaccine roll-out

419 worldwide, especially in low and middle income countries We searched PubMed for research articles

420 published between database inception and 22nd June 2021 using the search terms (COVID) AND

421 (Heterologous) AND (Vaccin*) NOT (BCG) with no language restrictions Beside our previously

422 published reactogenicity results,(14) we identified two animal studies using combinations of

423 messenger RNA, adenoviral vectored, inactivated and recombinant protein vaccines as prime boost

424 schedules Both studies showed robust humoral and cellular responses induced by heterologous

425 schedules in mice.(10,11) In addition, there were two clinical trials on the rAd26 and rAd5

vector-426 based heterologous prime-boost schedule (Sputnik V, Gamaleya Research Institute of Epidemiology

427 and Microbiology), showing good safety profiles, strong humoral/cellular responses and a 91.6%

428 vaccine efficacy.(8,9) A further clinical trial, which randomised participants primed with ChAd to

429 received BNT as the boost vaccine or no boost vaccination, reported robust immune response and

430 acceptable reactogenicity profile, but with no comparison to a homologous vaccine schedule.(12)

431 There were another two cohort studies evaluating ChAd prime and BNT boost schedules on medRxiv,

432 showing similar results.(13,26)

433 Added Value of this study

434 We report the results on the safety and immunogenicity of the first participant-blinded randomised

435 clinical trial using two vaccines approved by WHO for emergency use, ChAd and BNT, when

436 administered at a 28-day interval in heterologous and homologous vaccine schedules (ChAd/ChAd,

437 ChAd/BNT, BNT/BNT, BNT/ChAd) The cellular and humoral responses at 28 days post-boost of the

438 two heterologous vaccines schedules are no lower than the ChAd/ChAd schedule, which has shown

439 to be highly effective in preventing severe COVID-19 disease, and no safety concerns were raised

440 Implications of all the available evidence

441 In the era of multiple COVID-19 vaccines having approval for emergency use, the paramount issue in

442 solving the COVID-19 pandemic is now to optimise global vaccine coverage rate using the currently Preprint not peer reviewed

443 available vaccines The positive results from our study support flexibility in use of heterologous

prime-444 boost schedules using ChAd and BNT, which can contribute to the acceleration of vaccine roll-out

445 Further studies are needed examining more heterologous schedules, especially those vaccines being

446 deployed in low and middle-income countries

447

Preprint not peer reviewed

448 Author Contributions

449 MDS and JSN-V-T conceived the trial and MDS is the chief investigator MDS, AS, RHS, and XL

450 contributed to the protocol and design of the study AS, EP and RHS led the implementation of the

451 study XL and MG conducted the statistical analysis and have verified the underlying data AS, RHS,

452 MG, XL and MDS drafted the report All other authors contributed to the implementation and data

453 collection All authors reviewed and approved the final report

454 Declaration of interests

455 MDS acts on behalf of the University of Oxford as an Investigator on studies funded or sponsored by

456 vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen,

457 Medimmune, and MCM vaccines He receives no personal financial payment for this work JSN-V-T is

458 seconded to the Department of Health and Social Care, England AMC and DMF are investigators on

459 studies funded by Pfizer and Unilever They receive no personal financial payment for this work.AF is

460 a member of the Joint Committee on Vaccination and Immunisation and Chair of the WHO European

461 Technical Advisory Group of Experts (ETAGE) on Immunisation He is an investigator and/or provides

462 consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca,

463 Janssen, Valneva, Pfizer and Sanofi and of other vaccines from these and other manufacturers

464 including GSK, VPI, Takeda and Bionet Asia He receives no personal remuneration or benefits for any

465 of this work SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an

466 Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other

467 vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca,

468 GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and

469 antimicrobials He receives no personal financial payment for this work PTH acts on behalf of St

470 George’s University of London as an Investigator on clinical trials of COVID-19 vaccines funded or

471 sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax and Valneva He

472 receives no personal financial payment for this work CAG acts on behalf of University Hospitals

473 Birmingham NHS Foundation Trust as an Investigator on clinical trials and studies of COVID-19 and

474 other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca,

475 Novavax, CureVac, Moderna, and Valneva vaccines, and receives no personal financial payment for

476 this work VL acts on behalf of University College London Hospitals NHS Foundation Trust as an

477 Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers

478 including Pfizer, AstraZeneca and Valneva He receives no personal financial payment for this work TL

479 is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and is an occasional

Preprint not peer reviewed

480 consultant to Vaccitech unrelated to this work Oxford University has entered into a partnership with

481 AstraZeneca for further development of ChAdOx1 nCoV-19

482 Data sharing

483 The study protocol is provided in the appendix Individual participant data will be made available when

484 the trial is complete, upon requests directed to the corresponding author; after approval of a proposal,

485 data can be shared through a secure online platform

486 Acknowledgments

487 The study is funded by the UK Government through the National Institute for Health Research (NIHR)

488 and the Vaccine Task Force (VTF) This research was supported by the NIHR Oxford Biomedical

489 Research Centre and delivered through the NIHR funded National Immunisation Schedule Evaluation

490 Consortium (NISEC) MDS and SNF are NIHR Senior Investigators The views expressed are those of the

491 author(s) and not necessarily those of the NIHR or the Department of Health and Social Care The

492 investigators express their gratitude for the contribution of all the trial participants, the invaluable

493 advice of the international Data Safety Monitoring Board We additionally acknowledge the broader

494 support from the various teams within the University of Oxford including the Department of

495 Paediatrics, Clinical Trials Research Governance, Research Contracts and Public Affairs Directorate

496

497 Reference

4981 Impact of COVID-19 on people’s livelihoods, their health and our food systems [Internet] [cited 2021

499 Jun 10] Available from:

https://www.who.int/news/item/13-10-2020-impact-of-covid-19-on-500 people%27s-livelihoods-their-health-and-our-food-systems

5012 World Health Organization W Status of COVID-19 Vaccines within WHO EUL/PQ evaluation process

502 2021

5033 WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With

504 Vaccination Data [Internet] [cited 2021 Jun 5] Available from: https://covid19.who.int/

5054 India Situation Report [Internet] [cited 2021 Jun 10] Available from:

506 https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/india-situation-report

5075 Public Health Agency of Sweden F Information on the use of the Astra Zeneca vaccine in the

508 vaccination of people 65 and older [Internet] [cited 2021 May 20] Available from:

5126 French Health Authority HA de S Covid-19 : quelle stratégie vaccinale pour les moins de 55 ans ayant

513 déjà reçu une dose d’AstraZeneca ? [Internet] [cited 2021 May 20] Available from:

https://www.has-514

sante.fr/jcms/p_3260335/en/covid-19-quelle-strategie-vaccinale-pour-les-moins-de-55-ans-ayant-515 deja-recu-une-dose-d-astrazeneca

5167 Danish Health Authority S Denmark continues its vaccine rollout without the COVID-19 vaccine from

517 AstraZeneca [Internet] [cited 2021 May 20] Available from:

https://www.sst.dk/en/english/corona-518 eng/vaccination-against-covid-19/astrazeneca-vaccine-paused

5198 Logunov DY, Dolzhikova I V., Zubkova O V., Tukhvatullin AI, Shcheblyakov D V., Dzharullaeva AS, et al

520 Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19

521 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia The Lancet

522 2020 Sep 26;396(10255):887–97

5239 Logunov DY, Dolzhikova I v., Shcheblyakov D v., Tukhvatulin AI, Zubkova O v., Dzharullaeva AS, et al

524 Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine:

525 an interim analysis of a randomised controlled phase 3 trial in Russia The Lancet [Internet] 2021 Feb

526 20 [cited 2021 Jun 20];397(10275):671–81 Available from:

527 https://pubmed.ncbi.nlm.nih.gov/33545094/

52810 Spencer AJ, Mckay PF, Belij-Rammerstorfer S, Ulaszewska M, Bissett CD, Hu K, et al Heterologous

529 vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune

530 responses in mice

53111 He Q, Mao Q, An C, Zhang J, Gao F, Bian L, et al Heterologous prime-boost: breaking the protective

532 immune response bottleneck of COVID-19 vaccine candidates 2021;

53312 Borobia AM, Carcas AJ, Teresa Pérez Olmeda M, Castaño L, Bertrán J, García Pérez J, et al

534 Reactogenicity and immunogenicity of BNT162b2 in subjects having received a first dose of 1

535 ChAdOx1S: initial results of a randomised, adaptive, phase 2 trial (CombiVacS) 2

53613 Hillus D, Tober-Lau P, Hastor H, Helbig ET, Lippert LJ, Thibeault C, et al Reactogenicity of homologous

537 and heterologous prime-boost immunisation with BNT162b2 and ChAdOx1-nCoV19: a prospective

538 cohort study medRxiv 2021 May 22;2021.05.19.21257334

53914 Shaw RH, Stuart A, Greenland M, Liu X, Van-Tam JSN, Snape MD, et al Heterologous prime-boost

540 COVID-19 vaccination: initial reactogenicity data Lancet (London, England) [Internet] 2021 May 12

541 [cited 2021 May 21];0(0) Available from: http://www.ncbi.nlm.nih.gov/pubmed/33991480

54215 Bewley KR, Coombes NS, Gagnon L, McInroy L, Baker N, Shaik I, et al Quantification of SARS-CoV-2

543 neutralizing antibody by wild-type plaque reduction neutralization, microneutralization and

544 pseudotyped virus neutralization assays Nature Protocols Nature Research; 2021 p 1–33

54516 T-Cell Xtend [Internet] [cited 2021 Jun 16] Available from:

546 http://www.oxfordimmunotec.com/international/products-services/t-cell-xtend/

54717 Guidelines on Clinical Evaluation of Vaccines: Regulatory Expectations 2016

54818 D’Agostino RB, Massaro JM, Sullivan LM Non-inferiority trials: Design concepts and issues - The

549 encounters of academic consultants in statistics Statistics in Medicine 2003 Jan 30;22(2):169–86

55019 Voysey M, Costa Clemens SA, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al Single-dose

551 administration and the influence of the timing of the booster dose on immunogenicity and efficacy of Preprint not peer reviewed

553 [Internet] 2021 Mar 6 [cited 2021 May 21];397(10277):881–91 Available from:

554 https://doi.org/10.1016/

55520 AstraZeneca COVID-19 Vaccine AstraZeneca effective against Delta (‘Indian’) variant [Internet]

556 AstraZeneca Press Release 2021 [cited 2021 Jun 22] Available from:

557

https://www.astrazeneca.com/media-centre/press-releases/2021/covid-19-vaccine-astrazeneca-558 effective-against-delta-indian-variant.html#!

55921 Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al Safety and efficacy of the

560 ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised

561 controlled trials in Brazil, South Africa, and the UK Lancet (London, England) 2020 Dec 8;0(0)

56222 Lopez Bernal J, Andrews N, Gower C, Robertson C, Stowe J, Tessier E, et al Effectiveness of the

Pfizer-563 BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and

564 mortality in older adults in England: test negative case-control study 2021;

56523 Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, et al Effectiveness of

566 COVID-19 vaccines against the B.1.617.2 variant

56724 Stowe J, Andrews N, Gower C, Gallagher E, Utsi L, Simmons R, et al Effectiveness of COVID-19

568 vaccines against hospital admission with the Delta (B.1.617.2) variant [Internet] Public library - PHE

569 national - Knowledge Hub 2021 [cited 2021 Jun 22] Available from:

https://khub.net/web/phe-570

national/public-library/-571 /document_library/v2WsRK3ZlEig/view_file/479607329?_com_liferay_document_library_web_portl

572 et_DLPortlet_INSTANCE_v2WsRK3ZlEig_redirect=https%253A%252F%252Fkhub.net%253A443%252F

573 web%252Fphe-national%252Fpublic-library%252F-%25

57425 Hillus D, Schwarz T, Tober-Lau P, Hastor H, Thibeault C, Kasper S, et al Safety, reactogenicity, and

575 immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19

576 and BNT162b2: a prospective cohort study

57726 Groß R, Zanoni M, Seidel A, Conzelmann C, Gilg A, Krnavek D, et al Heterologous ChAdOx1 nCoV-19

578 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell

579 reactivity medRxiv [Internet] 2021 Jun 1 [cited 2021 Jun 5];2021.05.30.21257971 Available from:

580 https://www.medrxiv.org/content/10.1101/2021.05.30.21257971v1

58127 Ramasamy MN, Minassian AM, Ewer KJ, Flaxman AL, Folegatti PM, Owens DR, et al Safety and

582 immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and

583 old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial The Lancet 2020 Nov

584 19;396(10267):1979–93

58528 Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al Safety and Efficacy of the

586 BNT162b2 mRNA Covid-19 Vaccine The New England journal of medicine 2020 Dec 10;383(27)

58729 COVAX Booster and Mix & Match COVID-19 Vaccine Strategies - Planning Ahead in an Environment

588 of Increasing Complexity [Internet] [cited 2021 Jun 17] Available from:

59331 Mahase E Covid-19: Booster vaccine to be rolled out in autumn as UK secures 60m more Pfizer

594 doses BMJ (Clinical research ed) 2021 Apr 29;373:n1116

59532 Home | COV-Boost [Internet] [cited 2021 Jun 17] Available from:

596 https://www.covboost.org.uk/home

59733 Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA, et al Neutralizing antibody levels

598 are highly predictive of immune protection from symptomatic SARS-CoV-2 infection Nature Medicine

599 [Internet] 2021 May 17 [cited 2021 Jun 22];1–7 Available from:

https://doi.org/10.1038/s41591-600 021-01377-8

60134 Feng S, Phillips Mmath DJ, White Phd T, Sayal Phd H, Aley PK, Phd SB, et al Correlates of protection

602 against symptomatic and asymptomatic SARS-CoV-2 infection [cited 2021 Jun 24]; Available from:

603 https://doi.org/10.1101/2021.06.21.21258528

60435 Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al Efficacy and Safety of the

mRNA-605 1273 SARS-CoV-2 Vaccine New England Journal of Medicine 2020 Dec 30;

60636 Walsh EE, Frenck RW, Falsey AR, Kitchin N, Absalon J, Gurtman A, et al Safety and Immunogenicity of

607 Two RNA-Based Covid-19 Vaccine Candidates New England Journal of Medicine 2020 Oct

608 14;383:2439–50

60937 AstraZeneca ChAdOx1-S/nCoV-19 [recombinant], COVID-19 vaccine [Internet] [cited 2021 Jun 9]

610 Available from: https://www.who.int/publications/m/item/chadox1-s-recombinant-covid-19-vaccine

61138 Parry H, Bruton R, Stephens C, Brown, Zuo J, Moss P Extended interval BNT162b2 vaccination

612 enhances peak antibody generation in older people medRxiv [Internet] 2021 May 17 [cited 2021 Jun

613 24];2021.05.15.21257017 Available from: https://doi.org/10.1101/2021.05.15.21257017

61439 Coronavirus (COVID-19) Vaccinations - Statistics and Research - Our World in Data [Internet] [cited

615 2021 Jun 20] Available from: https://ourworldindata.org/covid-vaccinations

616

617

Preprint not peer reviewed