INTRODUCTION
The invention of COVID-19 vaccines represents probably the greatest success so far in the fight against the pandemic caused by the SARS-CoV2 virus. Despite numerous efforts and research, there is still no specific drug for the treatment of COVID-19. Therefore, it could be concluded that population vaccination and the acquisition of so-called "herd immunity" is currently the best way to combat this pandemic, or at least to slow it down.
However, like any other intervention or drug used in medicine, vaccines carry a certain risk of mild or severe side effects and allergic reactions. This may cause fear of vaccination in general or fear of vaccination with a particular type of vaccine against COVID-19. Furthermore, an additional problem is the necessity to produce and distribute huge quantities of vaccines, where delays in the production of individual vaccines could lead to delays in vaccination with the second dose. The third problem is the fact that the virus itself is prone to mutations and result in the emergence of new variants, some of which in the future may be resistant to immunity acquired by some or all previously available vaccines (1, 2). Do we have a solution to some of the above problems?
MIX AND MATCH
One of the potential solutions is the application of a "mix and match" vaccination regime. The name "mix and match" represents a well-known approach where one vaccine is used in the first vaccination, and then another vaccine in the re-vaccination. Regarding the available COVID-19 vaccines, this would mean the following: if a person is vaccinated with the first dose of one of the available mRNA vaccines (Pfizer- BioNTech or Moderna), then a vector vaccine can be used for the second dose (eg, AstraZeneca or Johnson & Johnson ), and the reverse approach is applicable where a person primarily vaccinated with a vector vaccine could be vaccinated with an mRNA vaccine. The idea behind such a vaccine combination approach is that different vaccines stimulate the immune system in different ways (because vaccines differ) and thus could trigger a more comprehensive and stronger immune response (1, 3). However, the question arises whether we have enough data or clinical studies that confirm that this approach is really effective and safe? According to the guidelines of the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) - not yet. Namely, the current position and recommendation of the WHO is that there is not enough data based on studies conducted so far to recommend this approach, so the current recommendation is to use the same vaccine for both doses, and the same position is shared by the US CDC (4, 5). However, some countries, such as Germany, Canada and Italy, have already approved the mix and match approach based on the data available so far (6).
WHAT DO THE DATA SAY? Unfortunately, there are still no published studies or peer-reviewed and publishe scientific articles in this regard. Nevertheless, unreviewed results and data from several studies conducted in Germany, Spain, and the United Kingdom are available online. A Spanish study was conducted on more than 600 subjects, and the data suggest that people vaccinated with Pfizer-BioNTech after receipt of the first dose of AstreZeneca have a significant increase in IgG antibody titers and the presence of neutralizing antibodies in 100% of subjects. Subjects developed common adverse reactions such as injection site pain, headache, and muscle aches, but no serious adverse reactions were reported. However, it should be noted that the study was conducted in people over 60 years of age and that there was no control group of persons vaccinated according to the currently approved protocol, ie with two doses of the same vaccine (eg AstraZeneca vaccine), which prevents comparisons of post-vaccination responses between the mix and match protocol and the standard vaccination protocol (7). Another study, conducted on a cohort of 340 health professionals in Germany, provides a partial answer to this question. In this study, subjects were vaccinated with two doses of Pfizer BioNTech vaccine or a combination of AstraZeneca (1st dose) / Pfizer-BioNTech (2nd dose). According to their preliminary analyzes, the combination of AstraZeneca / Pfizer-BioNTech vaccine is well tolerated (comparable number of systemic reactions to the vaccine with the group vaccinated with two doses of Pfizer-BioNTech vaccine), results in comparable immunogenicity with even slightly increased avidity (total binding strength) of IgG antibodies and a stronger T lymphocyte response in a mixed vaccination protocol (8). But the clinical significance of these findings is not yet clear. Similar results were obtained by other groups of researchers from Germany, with subjects receiving the AstraZeneca / Pfizer-BioNTech vaccine combination having a significantly higher number of specific CD4 and CD8 T lymphocytes with a high titer of neutralizing antibodies against several virus strains (B.1.1.7 , B.1.351 and P.1) (9, 10). Preliminary data from a multicenter randomized study conducted in the United Kingdom called Com-COV are also available (11). This study aims to examine several different mix and match vaccination protocols, including a group of subjects who will receive one of the available vector vaccines after an mRNA vaccine, which has not been studied so far. Preliminary data from this study show that the number of systemic adverse reactions in the mixed protocol after the second dose of vaccine is higher compared to standard protocols, which is inconsistent with data from other studies, but may be due to different age of included subjects or different time periods elapsed between two doses of COVID-19 vaccine (8).
In addition to the studies mentioned here, it is necessary to highlight two other clinical studies that are currently ongoing. The first is a US study conducted by the National Institute of Health (NIH), which, among other things, aims to examine the safety and efficacy of vaccination with a third dose of COVID-19 vaccine in people who are fully vaccinated according to the standard protocol. Subjects will receive a different vaccine for the third vaccine dose (mRNA vs vector vaccine). The significance of this study is reflected in the fact that it is still unknown whether additional re-vaccination will be required for those who have been vaccinated. In this regard, the use of a different vaccine could be of particular importance. Namely, the problem of frequent use of vector vaccines could be the development of an immune response to the vector itself, for example the adenovirus, where the person's immune system could eliminate the adenovirus, and thus the message it carries before it reaches cells, which could lead to reduced vaccine efficacy. On the other hand, a problem with mRNA vaccines can be created by the increased frequency of side effects with revaccination (12, 13). Another study is a Canadian study called MOSAIC, which aims to examine the safety and efficacy of COVID-19 vaccines with respect to the different time intervals between two doses of the same or different vaccines, and the duration of the protective effect in such conditions (14).
CONCLUSION The combination of different types of COVID-19 vaccines, if shown to be safe and effective, could be useful in several ways - it would enable vaccination of persons with history of severe immediate-type allergic reactions with a different type of vaccine as well as continuation of vaccination programs if problems in vaccine production or distribution arise. Preliminary data suggest that this regimen could lead to a stronger and more comprehensive immune response and thus provide greater protection against mutated strains of the virus as well. However, currently available data are too limited to recommend the "mix and match" vaccination regime, although it has been approved in a few countries. In addition, most studies addressing this question monitor the effects of vaccination when a vector vaccine (Vaxzevria) is used for the first dose and an mRNA vaccine for the 2nd dose. Data on the reverse order are extremely limited (Com-COV study). This is certainly an interesting approach for which there is a rational. We have to be patient and wait for the final results of ongoing clinical studies and evaluation of their results from the competent authorities. Until then, it should be pointed out once again that according to the current guidelines of all relevant health organizations, the benefits of vaccination with any available vaccine, if there are no contraindications, far outweigh the potential risks. Accordingly, we once again recommend vaccination as the best way to combat the COVID-19 pandemic.
What are the current recommendations in Croatia? The website of the Croatian Institute of Public Health states the possibility of an exception to the rule that both doses of vaccine should be from the same manufacturer; this is a situation when a person develops a serious side effect following the first dose of the vaccine (only Vaxzevria vector vaccine from AstraZenec is listed as an example) such as a bleeding disorder or thromboembolism that cannot be explained by another reason, etc. The physician who treated the side effect should be involved in the decision to vaccinate the patient with the same or a different vaccine (10).
References: 1. Covid-19 vaccine mixing: the good, the bad and the uncertain. https://www.clinicaltrialsarena.com/analysis/covid-19-vaccine-mixing-the-good-the-bad-and-the-uncertain/ . Access: 18.06.2021. 2. A mix-and-match approach to COVID-19 vaccines could provide logistical and immunological benefits. https://www.pbs.org/newshour/health/a-mix-and-match-approach-to-covid-19-vaccines-could-provide-logistical-and-immunological-benefits. Access: 21.06.2021. 3. COVID: Are mix-and-match vaccines the way forward? https://www.dw.com/en/mix-and-match-vaccines-biontech-astrazeneca-better-than-one-shot/a-57819127. Access: 21.06.2021. 4. Interim recommendations for use of the Pfizer–BioNTech COVID-19 vaccine, BNT162b2, under Emergency Use Listing. https://apps.who.int/iris/bitstream/handle/10665/341786/WHO-2019-nCoV-vaccines-SAGE-recommendation-BNT162b2-2021.2-eng.pdf?sequence=1&isAllowed=y. Access: 20.06.2021. 5. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fcovid-19%2Finfo-by-product%2Fclinical-considerations.html#Interchangeability. Access: 20.06.2021. 6. Factbox: Countries weigh 'mix and match' COVID-19 vaccines. https://www.reuters.com/world/middle-east/countries-weigh-mix-match-covid-19-vaccines-2021-05-24/ Access: 20.06.2021. 7. Borobia AM, i sur. Reactogenicity and immunogenicity of BNT162b2 in subjects having received a first dose of ChAdOx1S: initial results of a randomised, adaptive, phase 2 trial (CombiVacS). Dostupno putem linka: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3854768.
8. Hillus D, i sur. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study. Available through: https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2. 9. Barros-Martins J, i sur. Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Dostupno putem linka: https://www.medrxiv.org/content/10.1101/2021.06.01.21258172v1. 10. Schmidt T, i sur. Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens. Dostupno putem linka: https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1. 11. Shaw RH, i sur. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. Lancet. 2021;397(10289):2043-2046. doi: 10.1016/S0140-6736(21)01115-6. 12. NIH clinical trial evaluating mixed COVID-19 vaccine schedules begins. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-evaluating-mixed-covid-19-vaccine-schedules-begins. Access: 22.06.2021.
"MIX AND MATCH"CHens when you mix doses of the Pfizer and AstraZeneca vaccines? A new study is starting to reveal the answer. https://fortune.com/2021/05/12/what-happens-when-you-mix-doses-of-the-pfizer-and-astrazeneca-vaccines-a-new-study-is-starting-to-reveal-the-answer/. Access: 22.06.2021. 14. MOSAIC: Mix and Match COVID-19 Vaccines. https://centerforvaccinology.ca/study/mosaic-mix-and-match-covid-19-vaccines/ Pristup: 22.06.2021. 10. HZJZ. Privremena dopuna preporukama o cijepljenju protiv bolesti COVID-19. https://www.hzjz.hr/sluzba-epidemiologija-zarazne-bolesti/privremena-dopuna-preporukama-o-cijepljenju-protiv-bolesti-covid-19/ Access 6.7.2021."