key: cord-0942921-d2qrz98c
authors: Rashedi, Ronak; Samieefar, Noosha; Masoumi, Niloofar; Mohseni, Sahar; Rezaei, Nima
title: COVID‐19 vaccines mix‐and‐match: The concept, the efficacy and the doubts
date: 2021-11-30
journal: J Med Virol
DOI: 10.1002/jmv.27463
sha: 48085c25121679499fcb6f6c7d71a48052db6fd6
doc_id: 942921
cord_uid: d2qrz98c

The search for developing effective vaccines against SARS‐CoV‐2 began with the start of the COVID‐19 pandemic, and the first vaccine dose was administered in December 2020. Today, full vaccination of most of the world's population is considered the most important means to overcome the COVID‐19 pandemic. Vaccination has been associated with various struggles. Some adverse reactions have resulted in the discontinuation of the specific vaccines use in some countries. Countries in poor regions have faced difficulties supplying enough vaccine doses, and the emergence of new variants of concern has resulted in reduced effectiveness of available vaccines against COVID‐19. The mix‐and‐match strategy, using heterologous vaccines in the first and second doses, might successfully solve the mentioned struggles. Moreover, this strategy has been associated with higher cellular and humoral immune responses without significantly increasing the adverse reactions. Hence, this strategy can help improve the vaccines' effectiveness, and act as a solution for vaccine shortage in poor regions.

Finland, Sweden, United Arab Emirates, and Norway have been mixing COVID-19 vaccines. 5 Available data from Centers for Disease Control and Prevention (CDC) shows that vaccination is not distributed equally throughout the world and poorer nations are facing a lot of struggle to keep up with the vaccination program. 1, 6 Furthermore, mutations in the genome of SARS-CoV-2 and the emergence of new Variants of Concern (VOC), have resulted in reduced effectiveness of the available vaccines. 7 Previous studies on using heterologous vaccines in prime-boost immunization strategy have shown great success. Studies suggest that by evoking both cellular and humoral immune response, heterologous vaccines can result in 4-10 times higher T-cell responses. 8 Scientist are now convinced, that the mix-and-match approach can both solve the problem of vaccine shortage in poorer regions, and evoke greater immune response in the recipients. Hence, many countries have started mixing COVID-19 vaccine doses, using both the vaccines of the same platform for both doses or administering each dose with a vaccine of a different platform. 5, 7 2 | AVAILABLE VACCINES AGAINST COVID-19

Several vaccines are currently available in various countries to protect against COVID-19 infection. These vaccines are available on different platforms. A group of these vaccines contains nucleoside-modified messenger RNA (modRNA), from which we can name BNT162b2, developed by Pfizer/Biontech, a lipid nanoparticle formulation, nucleoside-modified messenger RNA (mRNA) that encodes full-length spike on the surface of the SARS-CoV-2 mutated form in the prefusion conformation, [9] [10] [11] and mRNA-1273, developed by Moderna, also a lipid-nanoparticle, which encodes prefusion-stabilized spike glycoprotein. 12 Another platform on which COVID-19 vaccines are made, is through the use of vectors, such as ChAdOx1 nCoV-19 or AstraZeneca vaccine (AZD1222), developed by Oxford University, a replication-deficient chimpanzee adenoviral vector, which contains the SARS-CoV-2 structural surface glycoprotein antigen gene, [13] [14] [15] [16] Gam-COVID-Vac vaccine (Sputnik V), a heterologous recombinant adenovirus (rAd)-based vaccine which carries the gene for SARS-CoV-2 full-length glycoprotein S (rAd26-S and rAd5-S), 17 There have been successful attempts of mixing COVID-19 vaccines in animals. In one study, the use of Sputnik V vaccine as the first dose and AstraZeneca as the second dose in mice showed that not only did this mixture not cause any particular problem, but it also resulted in higher immunity. 23 In another study in mice, the effect of using self-amplifying RNA vaccine (saRNA) and adenovirus carrier vaccine (ChAdOx1 nCoV-19/AZD1222) was investigated. The results of this study indicated that the antibody response in the use of these two types of vaccines is higher than using one type of vaccine for both doses. 24 After these successful animal studies, clinical trials began, Com-COV trial with more than 800 volunteers from oxford university demonstrated that mixing Oxford AstraZeneca and Pfizer

BioNTech induced a much more strong immune response. 31 Mix and match trials have not been reported severe side effects yet; a study in Spain shows that 448 people injected Oxford-AstraZeneca for the first dose, then Pfizer-BioNTech for the second dose; they had poor side effects; blood tests show coarse antibody response after two weak from the second shot. 25 Likewise, Charité, Saarland, and CombiVacS showed the same result, side effects of these vaccines were not worse than two shots of the same vaccine.

Nevertheless, the Com-COV study demonstrates that mixing vaccines could cause more side effects than prescribing two doses of the same vaccines. 26 Recent reports of COVID-19 vaccines mixing have been summarized in Table 2 accompanied by higher immunity both in animal models and humans. 36 This method has been used for HPV, HIV, influenza, Ebola, and also trials of HCV vaccines. [36] [37] [38] [39] Furthermore, mixing DNA vaccines with protein vaccines in trials of HSV, HIV, and HCV vaccines, mixing of protein and viral vaccines, and also virus-like particle vaccines with DNA vaccines have all been accompanied by higher immune responses. 40, 41 A number of possible mechanisms have been suggested for the higher immunity caused by the use of heterologous vaccines. It is recommended that by using dissimilar vaccine formulations, different arms of the immune system are evoked. Therefore, a combination of cellular and humoral immunity, as an instance, can result in higher and more prolonged immunity. It has also been seen that higher IgG levels, or neutralizing antibodies can be achieved using heterologous vaccines as these vaccines can evoke humoral immunity through different ways. 8 The underlying mechanism for higher immunity when mixing COVID-19 vaccines has not been clearly described. However, based on the results from available studies on incorporating COVID-19 vaccines, it is indicated that IgG antibodies, neutralizing antibodies, and also cellular immune response are significantly increased using heterologous COVID-19 vaccines compared to the homologous strategy. 27, 30, 42 This suggests that the same mechanism, long known for other heterologous vaccines,

can also be the underlying mechanism for the higher immune response achieved from mixing COVID-19 vaccines.

Shortage of vaccines, especially in poor regions, the emergence of new variants of concern that have been partially resistant to available vaccines, and a number of adverse reactions have forced several countries to mix the COVID-19 vaccines. 1, 7 This strategy has been associated with significant success. Studies have shown that mixing vaccines of different platforms can result in higher IgG and neutralizing antibodies as well as more strong cellular immune response. 27, 30, 42 Furthermore, using heterologous COVID-19 vaccines has resulted in higher neutralizing antibody levels against the VOC compared to the homologous vaccines. 42 As a result, both developing and industrialized countries have started taking the mix-and-match strategy into practice with the hope to immunize a greater percentage of their populations effectively against COVID- 19. 5 Studies and trials on mixing the available COVID-19 have been promising as they have been associated with a higher immune response without a significant increase in adverse reactions. Hence, this strategy can help improve the vaccines' effectiveness, as well as acting as a solution for vaccine shortage in poor regions.

All the authors had substantial contributions to the conception of the work. Drafting of the work was done by all the authors. All approved the final draft and agree to be accountable for all aspects of the work.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Ronak Rashedi https://orcid.org/0000-0003-2123-9419

Noosha Samieefar https://orcid.org/0000-0001-6429-7729

Nima Rezaei https://orcid.org/0000-0002-3836-1827

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