A comprehensive search was carried out in mainstream bibliographic databases or Medical Subject Headings, including ScienDirect, PubMed, Scopus, and ISI Web of Science. The search was applied to the articles that were published between January 2021 and November 2021. With strict literature search and screening processes, it yielded 10 articles from 136 articles of initial literature database. In June 2021, a preliminary study conducted by the University of Oxford scientists demonstrated that mixing the AstraZeneca and Pfizer vaccines produced a robust immune response against the SARS-CoV-2 (COVID-19) virus and induced higher antibodies than an only two-dose schedule of AstraZeneca vaccine and none of the groups demonstrated decreased neutralizing activity against the Alpha variant (UK variant), but the neutralization titer reduced by 2.5 to 6times against the Beta variant (South African variant), Gamma variant (Brazilian variant), and Delta variant (Indian variant). The Comparing COVID-19 Vaccine Schedule Combinations (Com-COV) study (463 cases of the 4-week interval group) revealed that immunization with AstraZeneca vaccine followed by Pfizer vaccine at the 4-week interval demonstrated a better immune response out of the two mixed dosing regimens. Com-COV study demonstrated in the earlier phase that around 30 % to 40 % of those who received mixed doses reported fevers after their second jab, compared to 10 % to 20 % of those who received the same vaccine for both doses. This result could be attributable to the shorter, 4-week interval between doses that was used during the Oxford study, whereas the safety data from a cohort with a 12-week dosing interval is still to appear.

In conclusion, it is better to give a different COVID-19 vaccine or mix-and-match COVID-19 vaccination than not administer the second dose at all.

Keywords: COVID-19, mix-and-match, mix, match, vaccine, vaccination

Com-COV, COVID-19 vaccine schedule combinations; COVID-19, coronavirus disease 2019; HIV, human immunodeficiency virus; SARS-CoV-2, Severe acute respiratory syndrome-coronavirus type 2; UK, united kingdom; USA, united states of america

 The objectives of this study is aimed to identify the feasibility of mixing and matching COVID-19 vaccination in the situation of shortage of COVID-19 vaccines.

Search strategy and inclusion criteria

A comprehensive search was carried out in mainstream bibliographic databases or Medical Subject Headings, including ScienDirect, PubMed, Scopus, ISI Web of Science, and websites of the news. The search was applied to the articles that were published between January 2021 and November 2021. Our first involved performing searches of article abstract/keywords/title using strings of [(“ Mix-and-match covid-19 vaccination ” or “ Mixing and matching ”, “ Vaccination ” and “ COVID-19 ”]. After a first approach of search, published articles focusing on COVID-19 were retained and the information on vaccine type and COVID-19 was extracted for having a crude knowledge involving their themes. Another round of publication search was conducted for adding the missing published articles that were not identified by the first round.

All keywords combinations from one disease type and climatic variable to bind the population of cases under consideration. Search string for disease groups include [ “ SARS-CoV-2 ” or “ COVID-19 ” or “ Vaccination ” or “ Vaccines ” or “ Mixing and Matching ” or “ Mix-and-Match ” ]. The initial literature databases were further manually screened with the following rules : 1) non-human infectious disease-related articles were excluded; 2) articles that did not report mix-and-match vaccination related to COVID-19 were not considered, such as commentary articles, or editorial; 3) non-peer reviewed articles were not considered to be of a scholarly trustworthy validity; and 4) duplicated and non-English articles were removed. The articles were carefully selected to guarantee the literature quality, which is a trade-off for quantity.

With strict literature search and screening processes, it yielded 10 articles from 136 articles of initial literature database. Needed article information was extracted from each article by : 1) direct information including journal, title, authors, abstract, full text documents of candidate studies, publishing year; 2) spatial scale and place name of the study area; 3) study period; 4) research method used; 5) type of COVID-19 vaccine studied; 6) types of mix-and-match vaccination studied; and 7) the conclusions made about the impacts of mix-and-match COVID-19 vaccination types on patients’ COVID-19 outcomes.

 In low-income and middle income countries, Ebola vaccine (Johnson & Johnson) experience demonstrated that mix-and-match vaccination is feasible, safety, and long-lasting immunization, adopted in phase I and phase II trials and can overcome easily with active community participation and suitable national planning.^1,2 In addition to Ebola, this concept has been previously implemented for influenza, malaria, and HIV.² The prime dose in the most of the current vaccination regimen is at a month interval followed by a second homologous booster dose.³ Recent interest in COVID-19 mixing vaccination is aimed to simplify countries’ facing fluctuation of various vaccine supplies and immunization efforts and increase SARS-CoV-2 (COVID-19) protection by delivery of the similar or same antigens of the disease-causing agent via two different vaccine types and eliciting a strong and long-lasting immune response as compared to the single vaccine regimen, but has a lack of evidence and a potential risk of increased-mixing-vaccine-adverse side effects³ that include increased headache, increased fever, increased malaise, increased joint pain, and increased AEFI, particularly in the elderly population.³

With strict literature search and screening processes, it yielded 10 articles from 136 articles of initial literature database. Needed article information was extracted from each article by : 1) direct information including journal, title, authors, abstract, full text documents of candidate studies, publishing year; 2) place name of the study area; 3) study period; 4) research method used; 5) type of mix-and-match COVID-19 vaccination studied; and 6) the conclusions made about the yields of mix-and-match COVID-19 vaccination on human protection of COVID-19. Seven published articles in this study revealed strongly support the benefit of the mix-and-match COVID-19 vaccination by increasing the neutralizing antibody levels and number of T-cell reactivity (such as, strongly neutralizing antibody against prevalent strain B.1.1.7 with heterologous prime boost was approximately 3.9-times higher than in those receiving homologous Pfizer vaccination; number of CD4+ and CD8+ T cells reacted to SARS-CoV-2 (COVID-19) spike peptide stimulus).

 In June 2021, a preliminary study conducted by the University of Oxford scientists demonstrated that mixing the AstraZeneca and Pfizer vaccines produced a robust immune response against the SARS-CoV-2 (COVID-19) virus and induced higher antibodies than an only two-dose schedule of AstraZeneca vaccine and none of the groups demonstrated decreased neutralizing activity against the Alpha variant (UK variant), but the neutralization titer reduced by 2.5 to 6times against the Beta variant (South African variant), Gamma variant (Brazilian variant), and Delta variant (Indian variant).⁴ The Comparing COVID-19 Vaccine Schedule Combinations (Com-COV) study (463 cases of the 4-week interval group) revealed that immunization with AstraZeneca vaccine followed by Pfizer vaccine at the 4-week interval demonstrated a better immune response out of the two mixed dosing regimens.⁴ Com-COV study demonstrated in the earlier phase that around 30 % to 40 % of those who received mixed doses reported fevers after their second dose, compared to 10 % to 20 % of those who received the same vaccine for both doses. This result could be attributable to the shorter, 4-week interval between doses that was used during the Oxford study, whereas the safety data from a cohort with a 12-week dosing interval is still to appear.⁴

The trials in Germany and Spain have also demonstrated that a mixed dosing regimen induced a better immune response than getting two doses of the AstraZeneca vaccination.⁴ In South Korea, the study on 100 actually-receiving-mixed-doses cases out of 499 cases conducted by the Korea Disease Control and Prevention Agency on a mixed vaccination, with AstraZeneca vaccine as the first dose and Pfizer vaccine as the second dose revealed the increased neutralizing antibody levels of 6times higher than those found after two doses of the AstraZeneca jab.⁴ Initial phase of Com-COV study or Com-COV1 study has been concentrated on mixing the AstraZeneca and Pfizer doses, whereas Com-COV2 study or phase 2 of the Com-COV study is assessing the immunogenicity and safety of combining the Moderna and Novavax vaccines with a first dose of either the Pfizer or AstraZeneca jab.⁴ Globally, COVID-19-dose-mixing studies on assessing other vaccine combinations are also ongoing, including a Russian trial of an AstraZeneca-Sputnik V combinations and a Philippines-based study mixing Sinovac’ s CoronaVac vaccination with 6 other vaccines.³ In India, COVID-19 mixing vaccination can assist in scaling up the vaccination drive to a large extent in this world’s-largest-COVID-19-vaccination-drive country.³

As of June 6, 2021, China, UK, and USA have began the COVID-19-vaccine mixing trials, but have not yet officially approved them due to not being designed to assess actual COVID-19 protection and non-corresponding-COVID-19-real-life protection of the studies’ antibody and T-cell measurements, whereas only Canada, Denmark, France, Germany, Norway, and Sweden implemented mixing vaccination to their citizens with rarely reported ChAdOx1 nCoV-19 (AstraZeneca) thromboembolic complications.^3,5 Whenever it is impossible to provide a second dose of COVID-19 vaccine, the Public Health of England guidelines recommend that it is better to give a different COVID-19 vaccine than not administer the second dose at all.,³ On July 12, 2021, the WHO’s chief scientist has suggested individuals against mixing and match in COVID-19 vaccines from different manufacturers.⁶

Nevertheless, on July 13, 2021, Thailand defended mixing two different COVID-19 vaccines to fight against a surge in SARS-CoV-2 (COVID-19) infections since COVID-19 outbreak in April 2021 after the WHO’s top scientist warned that it was a “ dangerous trend ” not backed by evidence.^5,7 Thailand’s health authorities will mix a first dose of the Chinese-produced “ Sinovac ” vaccination with a second dose of Astrazeneca vaccine to try and achieve a “ booster ” effect in 6weeks instead of 12weeks due to fast spreading disease (more than 353,700 reported- COVID-19-infected cases and 2,847 reported-COVID-19-related deaths in April 2021).⁷ Figure 1,⁸ Table 1⁸ and 2³ demonstrate different platforms of COVID-19 vaccines and mechanisms of antigen presentation, advantages and disadvantages of various platforms of COVID-19 vaccines, and recently published clinical trials and ongoing clinical trials on mixing COVID-19 vaccination( as of July 11, 2021), respectively.

Figure  1 Different platforms of COVID-19 vaccines and mechanisms of antigen presentation, and protective immunity generation.

Epidemiologists from Umeå University in Sweden analyzed their country’s data of COVID-19 and revealed that compared with unvaccinated people, 68 % of those on a mixed vaccination schedule were less likely to develop a symptomatic infection, whereas the 430,000 people with two doses of AstraZeneca vaccination were 50% less likely to have symptomatic infection. It clear that the heterologous regimens are more effective than two doses of AstraZeneca vaccination. Epidemiologists from the State Serum Institute in Copenhagen, Denmark identified that one dose of AstraZeneca vaccination followed by one dose of Pfize/BioNTech vaccination was 88% effective at preventing SARS-CoV-2 (COVID-19) infection, the effectiveness similar to that of two doses of Pfizer vaccination. Denmark stopped all use of the AstraZeneca vaccine in April 2021.^9,10

It is better to give a different COVID-19 vaccine or mixing and matching COVID-19 vaccination than not administer the second dose at all.

Dr. Attapon Cheepsattayakorn conducted the study framework and wrote the manuscript. Associate Professor Dr. Ruangrong Cheepsattayakorn and Dr. Thanom Jewsuebpong contributed to scientific content and assistance in manuscript writing. All authors read and approved the final version of the manuscript.

The authors declare that they have no actual or potential competing financial interests.

The authors disclose no funding sources

None.

1. Shaw RH, Stuart A, Greenland M, et al. Heterologous prime-boost COVID-19 vaccination : initial reactogenicity data. Lancet. 2021;397:2043‒2046.
2. GroB R, Zanoni M, Sei A. Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicit potent neutralizing antibody responses and T cell reactivity. medRxiv . 2021.
3. Kunal S, Sakthivel P, Gupta N, et al. Mix and match COVID-19 vaccines : potential benefit and perspective from India. Postgrad Med 2021.
4. Jimenez D. Pharmaceutical Technology Newsletter. COVID-19 vaccine mixing: has AZ/Pfizer emerged as a winning combo . 2021.
5. Grant K. MEDPAGETODAY. 2021.
6. Healthcare and Pharmaceuticals. 2021.
7. FRANCE 24. Thailand defends COVID vaccine “ mix-and-match ” after WHO warning. 2021.
8. Hwang JK, Zhang T, Wang AZ, et al. COVID-19 vaccines for patients with cancer: benefit likely outweigh risks. Journal of Hematology and Oncology . 2021; 14 : 38.
9. Callaway E. Nature News. Mix-and-match COVID-19 vaccines ace the effectiveness test. Nature. 2021.
10. Callaway E. Mix-and match COVID vaccines ace the effectiveness test. Nature. 2021.