Correspondence Heterologous (100 participants with additional 24 (21%) of 112 recipients of BNT for prime-boost COVID-19 visits), at baseline (before the prime both prime and boost (difference 21%, dose), at day 28 (before the boost 95% CI 8–33%). Similar increases were Published Online vaccination: initial dose) and 7 days post-boost, graded observed for chills, fatigue, headache, May 12, 2021 https://doi.org/10.1016/ according to a modified US Food joint pain, malaise, and muscle ache reactogenicity data S0140-6736(21)01115-6 and Drug Administration toxicity (figure; appendix). There were no There is significant international scale (appendix). All analyses are hospitalisations due to solicited See Online for appendix interest in heterologous prime-boost descriptive, as the study was not symptoms, and most of this increase in COVID-19 vaccination to mitigate powered for reactogenicity, with reactogenicity was observed in the 48 h against supply shocks or shortages endpoints reported as frequencies and after immunisation (appendix). that might otherwise reduce the speed percentages, together with absolute Participants were advised that of vaccine roll-out. Additionally, in differences between heterologous and paracetamol might reduce vaccine light of changing recommendations homologous vaccine schedules and side-effects but were not actively coun- regarding use of the ChAdOx1 nCoV-19 corresponding 95% CIs. selled to medicate prophylactically. (ChAd) COVID-19 vaccine (Vaxzevria, Recruitment commenced on Paracetamol use in the 48 h post-boost AstraZeneca), several countries are now Feb 11, 2021, and was completed on vaccine was reported by 40 (36%) of advising that individuals previously Feb 26, 2021, with 830 participants 112 recipients of ChAd for both prime primed with this vaccine should now enrolled and randomised from and boost, 63 (57%) of 110 recipients receive an alternative vaccine as 978 screened (the CONSORT flow of ChAd for prime and BNT for boost, their second dose, most commonly diagram is available in the appendix). 48 (41%) of 117 recipients of BNT for mRNA vaccines such as the BNT162b2 463 participants were randomly both prime and boost, and 68 (60%) (BNT) COVID-19 vaccine (Comirnaty, assigned to the four groups with a of 114 recipients of BNT for prime and Pfizer–BioNTech), administered in a 28-day prime-boost interval, and ChAd for boost, thereby mirroring the heterologous prime-boost schedule.1–3 367 participants randomised to reactogenicity pattern. To date there are no data on the groups with an 84-day prime-boost Haematology and biochemistry immunogenicity, reactogenicity, or interval. All 463 participants in the profiles were similar between hetero- safety of such schedules. Com-COV 28-day prime-boost interval group logous and homologous vaccine (ISRCTN 69254139) is a UK multi- received their prime vaccine, and schedules, with all laboratory adverse centre, participant-masked, randomised 461 participants received their boost events of grade 2 severity or less in heterologous prime-boost COVID-19 vaccine. Among the 463 participants, the heterologous vaccine schedule, vaccination study comparing all the median age was 57 years and no thrombocytopenia in any four prime-boost permutations of the (range 50–69), 212 (46%) participants group at day 7 post-boost (appendix). ChAd and BNT vaccines both at 28-day were female, and 117 (25%) from In this interim safety analysis, and 84-day prime-boost intervals. ethnic minorities, with baseline we found an increase in systemic Participants are 50 years and older with characteristics well balanced across reactogenicity after the boost no or mild-to-moderate, well controlled study groups. In groups with dose reported by participants in comorbidity and were recruited across homologous vaccine schedules, heterologous vaccine schedules in eight sites. The protocol is available systemic reactogenicity was greater comparison to homologous vaccine For the Com-COV protocol see online. after the prime dose in the ChAd schedules, and this was accompanied https://comcovstudy.org.uk/ study-protocol Following consultation with the group, and after the boost dose in the by increased paracetamol usage. Of study trial steering committee, here BNT group (figure). note, these data were obtained in we present the initial reactogenicity Both heterologous vaccine schedules participants aged 50 years and older, and safety data, ahead of the primary induced greater systemic reactogen- and reactogenicity might be higher immunological outcome, which is icity following the boost dose than in younger age groups4,5 for whom a projected to be available in June, 2021. their homologous counterparts, with mixed vaccination schedule is being Reactogenicity data presented here feverishness reported by 37 (34%) advocated in Germany, France, Sweden, consist of self-reported solicited local of 110 recipients of ChAd for prime Norway, and Denmark among those and systemic symptoms collected in and BNT for boost compared with who have received a ChAd prime the 7 days after both prime and boost 11 (10%) of 112 recipients of ChAd dose, in light of concerns regarding vaccination in participants randomised for both prime and boost (difference thrombotic thrombo cytopenia after to receive vaccines at 28-day intervals. 24%, 95% CI 13–35%). Feverishness the first dose of ChAd.6 Submissions should be Haematology and biochemistry safety was reported by 47 (41%) of Pending availability of a more made via our electronic submission system at monitoring blood results are also 114 recipients of BNT for prime and complete safety dataset and immuno- http://ees.elsevier.com/ reported from the immunology cohort ChAd for boost, compared with genicity results for heterologous thelancet/ www.thelancet.com Published online May 12, 2021 https://doi.org/10.1016/S0140-6736(21)01115-6 1 Correspondence Prime, local Hardness Itch Pain Redness Swelling Warmth 100 80 60 40 Percentage 20 0 Prime, systemic Chills Fatigue FeverFeverish Headache Joint pain 100 80 60 40 Percentage 20 0 Malaise Muscle ache Nausea Vomiting Diarrhoea 100 80 60 40 Percentage 20 0 Boost, local Hardness Itch Pain Redness Swelling Warmth 100 80 60 40 Percentage 20 0 Boost, systemic Chills Fatigue FeverFeverish Headache Joint pain 100 80 60 40 Percentage 20 0 Malaise Muscle ache Nausea Vomiting Diarrhoea BNT/BNT 100 ChAd/ChAdChAd/BNT BNT/ChAd Vaccine schedule 80 60 Severity 40 Mild Percentage Moderate 20 Severe 0 Hospitalisation BNT/BNT BNT/BNT BNT/BNT BNT/BNT BNT/BNT ChAd/ChAdChAd/BNT BNT/ChAd ChAd/ChAdChAd/BNT BNT/ChAd ChAd/ChAdChAd/BNT BNT/ChAd ChAd/ChAdChAd/BNT BNT/ChAd ChAd/ChAdChAd/BNT BNT/ChAd Vaccine schedule Vaccine schedule Vaccine schedule Vaccine schedule Vaccine schedule 2 www.thelancet.com Published online May 12, 2021 https://doi.org/10.1016/S0140-6736(21)01115-6 Correspondence prime-boost schedules (to be reported Oxford Vaccine Group, Centre for Clinical shortly), these data suggest that the Vaccinology and Tropical Medicine, University of Oxford, Oxford OX3 9DU, UK (RHS, AS, MG, XL, two heterologous vaccine schedules in MDS); Division of Epidemiology and Public Health, this trial might have some short-term School of Clinical Sciences, University of disadvantages. Routine prophylactic Nottingham, Nottingham, UK (JSNV-T) use of paracetamol after immunisation 1 Folkhälsomyndigheten - Public Health Agency 7 of Sweden. Information on the continued use of could help mitigate these and is being the Astra Zeneca vaccine in the vaccination of studied in Com-COV participants people 65 and older. March 26, 2021. http://www.folkhalsomyndigheten.se/the- receiving prime and boost vaccines public-health-agency-of-sweden/ at 12-week intervals. Regardless, it communicable-disease-control/covid-19/ is reassuring that all reactogenicity vaccination-against-covid-19/information-on- the-continued-use-of-the-astra-zeneca/ symptoms were short lived, and there (accessed April 29, 2021). were no concerns from the limited 2 Haute Authorité de Santé - French National Health Authority. Covid-19: quelle stratégie haematology and biochemistry data vaccinale pour les moins de 55 ans ayant déj available. Further studies evaluating reçu une dose d’AstraZeneca? April 9, 2021. heterologous prime-boost schedules, https://www.has-sante.fr/jcms/p_3260335/ en/covid-19-quelle-strategie-vaccinale-pour- incorporating vaccines manufactured les-moins-de-55-ans-ayant-deja-recu-une- by Moderna and Novavax, are ongoing, dose-d-astrazeneca (accessed April 29, 2021). 3 Sundhedsstyrelsen - Danish Health Authority. and are crucial to informing the Denmark continues its vaccine rollout without appropriateness of mixed COVID-19 the COVID-19 vaccine from AstraZeneca. vaccine schedules. April 14, 2021. https://www.sst.dk/en/english/ corona-eng/vaccination-against-covid-19/ MDS acts on behalf of the University of Oxford as an astrazeneca-vaccine-paused (accessed Investigator on studies funded or sponsored by April 29, 2021). vaccine manufacturers including AstraZeneca, 4 Polack FP, Thomas SJ, Kitchin N, et al. Safety GlaxoSmithKline, Pfizer, Novavax, Janssen, and efficacy of the BNT162b2 mRNA Covid-19 Medimmune, and MCM vaccines. He receives no vaccine. N Engl Med 2020; 383: 2603–15. personal financial payment for this work. All other 5 Ramasamy MN, Minassian AM, Ewer KJ, et al. authors declare no competing interests. RHS and AS Safety and immunogenicity of ChAdOx1 contributed equally. Members of the Com-COV nCoV-19 vaccine administered in a prime- study group are listed in the appendix. boost regimen in young and old adults (COV002): a single-blind, randomised, Robert H Shaw, Arabella Stuart, controlled, phase 2/3 trial. Lancet 2021; 396: 1979–93. Melanie Greenland, Xinxue Liu, 6 European Medicines Agency. AstraZeneca’s Jonathan S Nguyen Van-Tam, COVID-19 vaccine: EMA finds possible link to *Matthew D Snape, and the very rare cases of unusual blood clots with low blood platelets. April 7, 2021. https://www. Com-COV Study Group ema.europa.eu/en/news/astrazenecas-covid- [email protected] 19-vaccine-ema-finds-possible-link-very-rare- cases-unusual-blood-clots-low-blood (accessed April 29, 2021).