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Mix and match COVID-19 vaccines: potential benefit and perspective from India
  1. Shekhar Kunal1,
  2. Pirabu Sakthivel2,
  3. Nitesh Gupta3,
  4. Pranav Ish3
  1. 1 Cardiology, GIPMER, Delhi, India
  2. 2 Head and Neck Surgery & Oncology, All India Institute of Medical Sciences, New Delhi, Delhi, India
  3. 3 Department of Pulmonary, Critical Care and Sleep Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, Delhi, India
  1. Correspondence to Dr Pranav Ish, South Delhi, Delhi 110016, India; pranavish2512{at}

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Vaccination against COVID-19 infection has recently been launched all over the world. Getting the right vaccines into the right people at the right time during a pandemic is, unsurprisingly, proving to be a logistical challenge. There are multiple types of COVID-19 vaccines including inactivated virus, virtual vector-based and RNA-based vaccines. Most of the current vaccination regime includes a second homologous booster dose following a priming dose at a month interval. The recent interest in mixing of COVID-19 vaccines born of necessity stems for the aim of increased protection,1 simplifying immunisation efforts for countries facing fluctuating supplies of the various vaccines and its judicious utilisation, but has a risk of increased side effects and most importantly, a lack of evidence.

The concept of vaccine mixing is not something new but has been previously used for multiple illnesses including HIV, malaria, Ebola and influenza.2 ‘Heterologous prime-boost vaccination’ involves delivery of the same or similar antigens of the disease-causing agent through two different vaccine types with the first dosage being used to prime the immune system while the subsequent dosage using different vaccine types to boost the immune response. This aims to increase the protective efficacy and rationalise the usage of the available vaccines. Mixing two different vaccines can also elicit a strong and long-lasting immune response as compared with the single vaccine regimen. This was evident with the Ebola vaccine (Johnson & Johnson) wherein a mixed-dose approach was specifically adopted in phase I and phase II trials showing safety and long-lasting immunity. The first dose of the Ebola vaccine used the same adenovirus vector as in the AstraZeneca COVID-19 vaccine while the second dose used a Modified Vaccinia Ankara vector (modified poxvirus). Another benefit of this approach is to prevent the development of immunity by the virus against a particular viral vector-based vaccine. Some of the vaccines currently approved for COVID-19 including Sputnik V, Johnson & Johnson and AstraZeneca use a modified adenovirus as a vector to deliver the SARS-CoV-2 spike protein to evoke an immune response. However, with subsequent doses there is a possibility of developing an immune response against the adenovirus vector thereby dampening the effect of viral vector-based vaccines. This can be circumvented with the use of different platforms for antigen delivery such as mRNA-based (Pfizer or Moderna) or protein-based (Novavax) in second and subsequent booster doses.

The potential risks involved in vaccine mixing include increased side effects reported as adverse events following immunisation (AEFI). Increased fever, headache, joint pain, malaise have been reported in elderly population receiving mixed vaccination. However, the increased AEFI have infrequently required hospitalisation and were associated with a preserved haematological profile, biochemical profile and a quick clinical recovery. It has been postulated that this increase in side effects may even be greater in the younger population due to greater systemic reactogenicity. Heterologous vaccination regimen leads to the added complexity in terms of differences in shelf life and storage conditions of the two different vaccines used. Another important aspect to consider is the regulatory complications involved in mixing two different vaccines. However, experience from the Ebola vaccination has shown that mix and match vaccination is feasible in low-income and middle-income countries and these bottlenecks can easily be overcome with proper planning and active community participation.3

The evidence for COVID-19 mixing is scanty and is limited to com-COV1, CombiVacS and a few small observational studies. Table 1 summarises the published literature and the ongoing trials.1–4 Until 6 June 2021, only Canada, France, Germany, Denmark, Norway and Sweden are the few countries advocating mixing of vaccines to its citizens in the light of rare thrombotic complications with ChAdOx1 nCoV-19 vaccine (AstraZeneca). The USA, the UK and China have started trials for vaccine mixing but have not officially approved them yet. However, these recent studies are imperfect because they are not designed to assess actual protection against COVID-19. The antibody and T-cell measurements the studies rely on do not correspond to real-life protection.

Table 1

Published and ongoing studies on COVID-19 vaccine mixing across the world

The world’s largest vaccination drive which started on 16 January 2021 in India has covered over 170 million for the first vaccine dose. India has a huge population of over 1.3 billion and it shall take years to get the entire population fully vaccinated if vaccination continues at the same pace. There are undeniable bottlenecks in the supply chain and barriers to overcome if the remaining population is to be fully vaccinated anytime soon. Until 2 June 2021, only 43% of the population above 60 years, and 37% of the population aged 45–60 years has been covered by at least one dose of vaccine.5 Vaccination of people below 45 years of age has only recently started. Thus, mixing of vaccines can help in scaling up the vaccination drive to a large extent. It can also ensure that each person gets two doses of vaccine. Even the Public Health England guidelines recommend that whenever it is not possible to give a second dose, it is better to administer a different COVID-19 vaccine than not give the second dose at all.

As the world races to vaccinate as many people as possible against COVID-19, mixing vaccines could be magic bullets against the ‘just really embarrassing’ inequality in global vaccine access. We strongly believe mixing vaccines will soon be the reality for many countries around the world aiming to make best use of the vaccines available to them. However, all attempts for vaccine mixing must be evaluated under strict vigilance, preferably in a clinical trial mode to generate more evidence regarding safety and efficacy.

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  • Contributors PI and SK were involved in conceptualisation, literature search. PI, SK, NG and PS were involved in writing, review and editing. All authors have read and agreed to the final draft submitted.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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