Letter Postgrad Med J: first published as 10.1136/postgradmedj-2021-140648 on 22 July 2021. Downloaded from Mix and match COVID-19 of developing an immune response against in the supply chain and barriers to over- the adenovirus vector thereby dampening come if the remaining population is to : potential benefit the effect of -­based vaccines. be fully vaccinated anytime soon. Until 2 and perspective from India This can be circumvented with the use of June 2021, only 43% of the population different platforms for antigen delivery above 60 years, and 37% of the popula- such as mRNA-­based (Pfizer or Moderna) tion aged 45–60 years has been covered 5 against COVID-19 or protein-­based () in second and by at least one dose of . Vaccina- has recently been launched all over the subsequent booster doses. tion of people below 45 years of age has world. Getting the right vaccines into the The potential risks involved in vaccine only recently started. Thus, mixing of right people at the right time during a mixing include increased side effects vaccines can help in scaling up the vacci- pandemic is, unsurprisingly, proving to be reported as adverse events following nation drive to a large extent. It can also a logistical challenge. There are multiple immunisation (AEFI). Increased fever, ensure that each person gets two doses of headache, joint pain, malaise have types of COVID-19 vaccines including vaccine. Even the England been reported in elderly population inactivated virus, virtual vector-­based and guidelines recommend that whenever it receiving mixed vaccination. However, RNA-­based vaccines. Most of the current is not possible to give a second dose, it is the increased AEFI have infrequently vaccination regime includes a second better to administer a different COVID-19 required hospitalisation and were asso- homologous following a vaccine than not give the second dose at ciated with a preserved haematological priming dose at a month interval. The all. profile, biochemical profile and a quick recent interest in mixing of COVID-19 As the world races to vaccinate as many clinical recovery. It has been postulated people as possible against COVID-19, vaccines born of necessity stems for the 1 that this increase in side effects may even mixing vaccines could be magic bullets aim of increased protection, simplifying be greater in the younger population due against the ‘just really embarrassing’ immunisation efforts for countries facing to greater systemic . Heter- inequality in global vaccine access. We fluctuating supplies of the various vaccines ologous vaccination regimen leads to strongly believe mixing vaccines will soon and its judicious utilisation, but has a risk the added complexity in terms of differ- be the reality for many countries around of increased side effects and most impor- ences in shelf life and storage condi- the world aiming to make best use of the tantly, a lack of evidence. tions of the two different vaccines used. vaccines available to them. However, all The concept of vaccine mixing is not Another important aspect to consider is attempts for vaccine mixing must be eval- something new but has been previously the regulatory complications involved in uated under strict vigilance, preferably used for multiple illnesses including HIV, mixing two different vaccines. However, in a mode to generate more malaria, and influenza.2 ‘Heterol- experience from the Ebola vaccination evidence regarding safety and efficacy. ogous prime-boost­ vaccination’ involves has shown that mix and match vacci- delivery of the same or similar antigens nation is feasible in low-income­ and Shekhar Kunal ‍ ‍ ,1 Pirabu Sakthivel ‍ ‍ ,2 of the disease-causing­ agent through middle-­income countries and these Nitesh Gupta,3 Pranav Ish ‍ ‍ 3 two different vaccine types with the first bottlenecks can easily be overcome with 1Cardiology, GIPMER, Delhi, India dosage being used to prime the immune 2 proper planning and active community Head and Neck Surgery & Oncology, All India Institute system while the subsequent dosage participation.3 of Medical Sciences, New Delhi, Delhi, India 3 using different vaccine types to boost the The evidence for COVID-19 mixing Department of Pulmonary, Critical Care and Sleep http://pmj.bmj.com/ immune response. This aims to increase Medicine, Vardhman Mahavir Medical College and is scanty and is limited to com-­COV1, Safdarjung Hospital, New Delhi, Delhi, India the protective efficacy and rationalise the CombiVacS and a few small observational usage of the available vaccines. Mixing two studies. Table 1 summarises the published Correspondence to Dr Pranav Ish, South Delhi, Delhi 110016, India; pranavish2512@​ ​gmail.com​ different vaccines can also elicit a strong literature and the ongoing trials.1–4 Until and long-­lasting immune response as 6 June 2021, only Canada, France, Contributors PI and SK were involved in compared with the single vaccine regimen. conceptualisation, literature search. PI, SK, NG and PS Germany, Denmark, Norway and Sweden were involved in writing, review and editing. All authors This was evident with the Ebola vaccine are the few countries advocating mixing of have read and agreed to the final draft submitted. on September 28, 2021 by guest. Protected copyright. (Johnson & Johnson) wherein a mixed-­ vaccines to its citizens in the light of rare Funding The authors have not declared a specific dose approach was specifically adopted thrombotic complications with ChAdOx1 grant for this research from any funding agency in the in phase I and phase II trials showing nCoV-19 vaccine (AstraZeneca). The public, commercial or not-­for-­profit sectors. safety and long-lasting­ immunity. The first USA, the UK and China have started trials Competing interests None declared. dose of the Ebola vaccine used the same for vaccine mixing but have not officially Patient consent for publication Not required. adenovirus vector as in the AstraZeneca approved them yet. However, these recent COVID-19 vaccine while the second dose Provenance and peer review Not commissioned; studies are imperfect because they are internally peer reviewed. used a vector not designed to assess actual protection (modified poxvirus). Another benefit of against COVID-19. The antibody and this approach is to prevent the develop- T-cell­ measurements the studies rely on do This article is made freely available for use in ment of immunity by the virus against accordance with BMJ’s website terms and conditions not correspond to real-­life protection. for the duration of the covid-19 pandemic or until a particular viral vector-based­ vaccine. The world’s largest vaccination drive otherwise determined by BMJ. You may use, download Some of the vaccines currently approved which started on 16 January 2021 in India and print the article for any lawful, non-­commercial for COVID-19 including Sputnik V, has covered over 170 million for the first purpose (including text and data mining) provided that Johnson & Johnson and AstraZeneca vaccine dose. India has a huge population all copyright notices and trade marks are retained. use a modified adenovirus as a vector to of over 1.3 billion and it shall take years © Author(s) (or their employer(s)) 2021. No commercial deliver the SARS-­CoV-2 spike protein to to get the entire population fully vacci- re-­use. See rights and permissions. Published by BMJ. evoke an immune response. However, nated if vaccination continues at the same with subsequent doses there is a possibility pace. There are undeniable bottlenecks

Postgrad Med J Month 2021 Vol 0 No 0 1 Letter Postgrad Med J: first published as 10.1136/postgradmedj-2021-140648 on 22 July 2021. Downloaded from

Table 1 Published and ongoing studies on COVID-19 vaccine mixing across the world Published studies Study name/authors/site/ S.No. number of participants Type of study Vaccines and group Outcomes Adverse effects 1. CombiVacS/Borobia et al1/ Randomised, phase Trial arm: Trial arm: greater immune response: 150 times Similar in both groups Spain/n=663 II trial Prime: ChAdOx1 nCoV- antibody 14 days post second dose, Fourfold mild: (68.3%); moderate: (29.9%) 19 vaccine (Vaxzevria, increase in cellular immune response, effective in Most common: headache (44%), malaise AstraZeneca); protecting against SARS-­CoV-2 (41%), chills (25%), mild nausea (11%), Boost: BNT162b2 vaccine Control arm: antibody titres at 14 days similar to mild cough (7%) and fever (2.5%) (Comirnaty, Pfizer-­BioNTech) baseline titres Control arm: received only one dose and not received any second dose of vaccine 2. Groß et al2/Germany/n=26 Prospective, First dose: ChAdOx1 nCoV-19 ►► Strong neutralisation titres 2 weeks post Prime dose: mild to moderate reaction: observational study (AstraZeneca) BNT162b2 boost 88.4% Second dose: BNT162b2 (Pfizer/ ►► Neutralising activity against prevalent strain Boost dose: mild or moderate symptom: BioNTech) after 8-­week interval B.1.1.7 with heterologous prime boost was 80.8% No control group 3.9-­fold higher than in individuals receiving Common symptoms: pain at the injection homologous BNT162b2 vaccination site, fatigue, headache, chills, myalgia ►► CD4+ and CD8+ T cells reacted to SARS-CoV­ -2 and fever spike peptide stimulus 2 weeks post full vaccination 3. Com-COV­ trial/Shaw et al3/ Single-blind,­ Trial arm: Arm 1: Prime: Not reported Greater systemic reactogenicity in UK/n=830 randomised, phase ChAdOx1 nCoV-19 vaccine heterologous prime-­boost regimen than II trial (Vaxzevria, AstraZeneca); Boost: their homologous counterparts BNT162b2 vaccine (Comirnaty, Most common symptom: Feverishness Pfizer-BioNTech)­ No hospitalisations Arm 2: Prime: BNT162b2 Most of increased reactogenicity vaccine; Boost: ChAdOx1 nCoV- observed within 48 hours after 19 vaccine immunisation Control arm: homologous schedules Arm 1: Prime and boost: BNT162b2 vaccine Arm 2: Prime and boost: ChAdOx1 nCoV-19 vaccine 4. EICOV-COVIM­ Study/Hillus et Prospective, Arm 1: ►► Serum antibody responses: strongly increased Local reaction: slight higher frequency al4/Germany/n=340 observational cohort Prime: ChAdOx1 nCoV-19 after both homologous and heterologous after heterologous ChAdOx/ BNT162b2 study vaccine (AstraZeneca); Boost: boost booster compared with homologous BNT162b2 vaccine (Pfizer-­ ►► Neutralising antibody response rate 3 week BNT162b2/BNT162b2 booster BioNTech) 10–12 weeks apart post boost immunisation: homologous Systemic reactions: Most frequent after Arm 2: BNT162b2 (99.01%); heterologous ChAdOx/ prime immunisation with ChAdOx (86%) Homologous BNT162b2 vaccine BNT162b2 boost: 100.00% and less frequent after homologous (prime and boost) 3 weeks apart ►► S1-­IgG avidity: high after heterologous BNT162b2/BNT162b2 (65%) or ChAdOx/BNT162b2 boost compared with heterologous ChAdOx/BNT162b2 booster homologous BNT162b2/BNT162b2 boost vaccination (48%) http://pmj.bmj.com/ ►► T-­cell reactivity: significantly higher after ►► No potentially life-­threatening heterologous ChAdOx/BNT162b2 boost reactions after any of the vaccine compared with homologous BNT162b2/ regimens BNT162b2 boost

Ongoing studies Type and aim of

S.No. Study/site/participants study Vaccines and group Primary and secondary outcomes Current status on September 28, 2021 by guest. Protected copyright. 5. MOSAIC (NCT04894435)/ Randomised clinical Multiple groups (13): comparing n=1300 participants Ongoing Canada/n=1300 participants trial various combination of Primary outcome measures: Aim: assess the Moderna mRNA vaccine, Antibody response to SARS-CoV­ -2 S protein at 28 immune response Pfizer/BioNTech mRNA vaccine days after second dose of vaccine and safety of two and Secondary outcome measures: different vaccines Astra Zeneca in homologous 1. Durability of antibody response to SARS-­ for first and second and heterologous prime-­boost CoV-2 S protein over 12 months doses as well as for regimen 2. Pseudoneutralisation assay, T-­cell testing, differing intervals ADCC, antibody avidity between the first and second dose of 3. Incidence of grade 3 solicited local and two-dose­ vaccine systemic adverse events, SAEs, AEFIs, in the 7 days following vaccine receipt 4. Description of safety outcomes over 12 months post-­vaccination including SAEs

Continued

2 Postgrad Med J Month 2021 Vol 0 No 0 Letter Postgrad Med J: first published as 10.1136/postgradmedj-2021-140648 on 22 July 2021. Downloaded from

Table 1 Continued

Ongoing studies Type and aim of S.No. Study/site/participants study Vaccines and group Primary and secondary outcomes Current status 6. NIH trial, USA Phase 1/2, open-­ Vaccines: mRNA-1273 n=400 participants planned Ongoing (NCT04889209) label clinical trial (ModernaTX), BNT162b2 (Pfizer/ Primary outcome: Aim: assess safety, BioNTech) or Ad26.COV2.S 1. Magnitude of SARS-­CoV-2 specific reactogenicity and (/ antibody binding and neutralisation titre immunogenicity Johnson & Johnson) 2. Occurrence of adverse events following of a delayed (>12 Booster shot after complete delayed booster vaccination weeks) vaccine vaccination will be given in boost various combinations though 3. Occurrence of serious adverse event after multiple arms of the study last dose on study 4. Response rate of SARS-­CoV-2 specific antibody binding and neutralisation titres 7. China (NCT04892459) Randomised, Trial arm: n=300 participants planned Ongoing parallel-controlled­ Prime: Inactive SARS-­CoV-2 Primary outcomes: trial vaccine (Vero cell) (Sinovac 1. Adverse reactions within 28 days after the Aim: safety and Research & Development Co., booster dose immunogenicity Ltd.); Boost: Recombinant SARS-­ 2. GMT of neutralising antibodies against live of sequential CoV-2 Ad5 vectored vaccine SARS-­CoV-2 virus on day 14 after booster immunisation of (CanSino Biologics) a recombinant Comparator arm: Homogeneous dose SARS-CoV-2­ vaccine boost arm with inactive vaccine (adenovirus type 5 vector) 8. France (NCT04900467) Randomised, open Arm 1: n=400 participants Ongoing label, non-­inferiority Prime: Pfizer mRNA vaccine; Primary outcome: trial Boost: Moderna mRNA vaccine anti-­Spike IgG titre 28 days post vaccination in Aim: compare vs Prime: Pfizer; Boost: Pfizer both arms immunological vaccine Secondary outcome: adverse events efficacy of Arm 2: heterologous prime Prime: Moderna mRNA vaccine; boost regimen Boost: Pfizer mRNA vaccine vs with homologous Prime: Moderna mRNA vaccine; vaccination Boost: Moderna mRNA vaccine 9. Austria (NCT04907331) Randomised control Trial arm: n=3000 participants Ongoing trial, Phase II Prime: ChAdOx1 nCoV- Primary outcomes: Aim: safety 19 vaccine (Vaxzevria, 1. Neutralising antibodies in both arms and efficacy of AstraZeneca); 2. T-­cells response to SARS-­CoV-2 S protein heterologous Boost - BNT162b2 vaccine epitopes in in both arms vaccination (Comirnaty, Pfizer-­BioNTech) 12 3. Vaccine failures in both the arms with Vaxzevria weeks apart (ChAdOx1-S,­ Control arm: Homolog AZ) followed Vaccination with Vaxzervria http://pmj.bmj.com/ by Comirnaty (Prime/Boost) or Comirnaty (BNT162b2, Pfizer/ (Prime/Boost) BioNTech) ADCC, antibody-­dependent cellular cytotoxicity; AEFI, adverse events following immunisation; CD, cluster of differentiation; GMT, geometric mean titre ; IgG, immunoglobulin G; mRNA, messenger RNA; S protein, spike protein; SAE, serious adverse event.

To cite Kunal S, Sakthivel P, Gupta N, et al. Pranav Ish http://orcid.​ ​org/0000-​ ​0003-1701-​ ​4970 3 Shaw RH, Stuart A, Greenland M, et al. Heterologous

Postgrad Med J Epub ahead of print: [please include prime-­boost COVID-19 vaccination: initial reactogenicity on September 28, 2021 by guest. Protected copyright. Day Month Year]. doi:10.1136/ data. Lancet 2021;397:2043–6. postgradmedj-2021-140648 REFERENCES 4 Hillus D, Schwarz T, Tober-Lau­ P. Safety, reactogenicity, 1 Borobia AM, Carcas AJ, Olmeda P. Reactogenicity and immunogenicity of homologous and heterologous Accepted 11 July 2021 and immunogenicity of BNT162b2 in subjects having prime-­boost immunisation with ChAdOx1-­nCoV19 and Postgrad Med J 2021;0:1–3. received a first dose of ChAdOx1s: initial results of BNT162b2: a prospective cohort study. medRxiv 2021. doi:10.1136/postgradmedj-2021-140648 a randomised, adaptive, phase 2 trial (CombiVacS). 5 Dey S. More people in India received at least one dose Available: https://​ssrn.com/​ ​abstract=3854768​ of Covid vaccine than in US: Govt. The Times of India, ORCID iDs 2 Groß R, Zanoni M, Seidel A. Heterologous ChAdOx1 2021. Available: https://timesofindia. indiatimes. com/ Shekhar Kunal http://orcid.​ ​org/0000-​ ​0002-0319-​ ​9241 nCoV-19 and BNT162b2 prime-­boost vaccination india/more-people-in-india-received-at-least-one- Pirabu Sakthivel http://orcid.​ ​org/0000-​ ​0002-6941-​ ​ elicits potent neutralizing antibody responses and T cell dose-of-covid-vaccine-than-in-us-govt/articleshow/​ 9892 reactivity. medRxiv 2021. 83243142.cms​ [Accessed 7 Jun 2021].

Postgrad Med J Month 2021 Vol 0 No 0 3