In December 2019, the Chinese health authorities declared an outbreak of the novel coronavirus 2019 (COVID-19). A significant difference in the number of COVID-19 cases and mortality has been noted among the different World Health Organization (WHO) regions and countries.

This discrepancy could be attributed to several factors such as prevalence of testing in a population, lack of reporting in some countries, the population demographics and particularly the number of elderly making up the population and finally, the vaccination schedule. Various vaccines were discussed in the literature to be possible protective measures against COVID-19 [1Cascella M, Rajnik M, Cuomo A, et al. Features, Evaluation and Treatment Coronavirus (COVID-19).StatPearls 2020. Updated 2020 Mar 20 Internet Available at: https://www.ncbi.nlm.nih.gov/books/ NBK554776/, 2McIntosh K. Coronavirus disease 2019. Available at: https://www. uptodate.com/contents/coronavirus-disease-2019-covid- 19].

Table 1 summarizes the vaccination schedules of 2 countries from WHO Europe Region (Italy and Spain) and 2 countries from WHO Regional Office for the Eastern Mediterranean (Iran and Egypt).

Recently, it was hypothesized that the BCG vaccine may potentially be protective against COVID-19, particularly in youth below the age of 18 [6de Vrieze J. Can a century-old TB vaccine steel the immune system against the new coronavirus? Science 2020.
[http://dx.doi.org/10.1126/science.abb8297] , 7Sharma AR, Batra G, Kumar M, et al. BCG as a game-changer to prevent the infection and severity of COVID-19 pandemic? Allergol Immunopathol (Madr) 2020; S0301-0546(20): 30106-.]. For instance, countries that do not include the BCG vaccine, such as Italy and Spain, have reported a large number of COVID-19 cases as well as deaths. Spain included BCG vaccine in its routine vaccination program till the early 1980s [8 Available at: https://www.mscbs.gob.es/profesionales/saludPublica/ prevPromocion/PlanTuberculosis/docs/PlanTB2019.pdf]. However, Iran which includes BCG in its obligatory vaccination schedule has also reported a large number of cases of COVID-19. Of note, Wuhan (China), where this pandemic was first found, also includes the BCG vaccine in its routine vaccination schedule [9Hu Y, Chen Y. Evaluating Childhood Vaccination Coverage of NIP Vaccines: Coverage Survey versus Zhejiang Provincial Immunization Information System. Int J Environ Res Public Health 2017; 14(7)E758
[http://dx.doi.org/10.3390/ijerph14070758] [PMID: 28696387] ]. Therefore, the protective effect of BCG against COVID-19 may not correlate. From 12 April 2020 to date WHO has not confirmed if the BCG vaccine is protective against COVID-19 [10WHO Scientific Brief 2020. Available at: https://apps.who.int/ iris/bitstream/handle /10665/331745/WHO-2019-nCoV-Sci_Brief-BCGvaccination-2020.1-eng.pdf?sequence=1&isAllowed=y]. A recent cohort study of 5933 adults aged 35 to 41 years showed no statistically significant difference in the proportion of positive COVID-19 test results in the BCG-vaccinated group vs the unvaccinated group [11Hamiel U, Kozer E, Youngster I. SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA 2020; 323(22): 2340-1.
[http://dx.doi.org/10.1001/jama.2020.8189] [PMID: 32401274] ].

Both Iran and Egypt included the Sabin vaccine (live attenuated oral poliomyelitis vaccine) under the obligatory vaccination program; meanwhile, Italy and Spain used Salk vaccine (inactivated IM poliomyelitis vaccine). Sabin vaccine simulates natural infection because it induces both circulating antibodies and intestinal resistance. Thus it immunizes susceptible contacts through secondary spread. On the contrary, Salk vaccine gives only circulating antibodies [12Bockstal V, Tiemessen MM, Achterberg R, et al. An inactivated poliovirus vaccine using Sabin strains produced on the serum-free PER.C6® cell culture platform is immunogenic and safe in a non-human primate model. Vaccine 2018; 36(46): 6979-87.
[http://dx.doi.org/10.1016/j.vaccine.2018.09.068] [PMID: 30314910] , 13Parker EP, Molodecky NA, Pons-Salort M, O’Reilly KM, Grassly NC. Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame. Expert Rev Vaccines 2015; 14(8): 1113-23.
[http://dx.doi.org/10.1586/14760584.2015.1052800] [PMID: 26159938] ]. Recently, Iran and Egypt added a single dose of the Salk vaccine at 5 months of age to the 6-7 doses of Sabin vaccine because of the new evidence showing that the use of Salk vaccine in conjunction with Sabin vaccine achieves better mucosal immunity [4WHO vaccine-preventable diseases: monitoring system 2019 . Available at: https:// apps.who.int/immunization_monitoring/ global summary/countries?countrycriteria%5Bcountry%5D%5B%5D=IRN&commit=OK, 13Parker EP, Molodecky NA, Pons-Salort M, O’Reilly KM, Grassly NC. Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame. Expert Rev Vaccines 2015; 14(8): 1113-23.
[http://dx.doi.org/10.1586/14760584.2015.1052800] [PMID: 26159938] ].

Table 1
Comparison between 2 countries from who europe region and 2 countries from WHO regional office for the eastern mediterranean regarding COVID-19 data and vaccination schedules.

These differences in the vaccination schedules among the 4 studied countries and the number of COVID-19 cases suggest that Sabin vaccine could have produced cross-immunity at the community level, explaining the comparative number of cases and deaths.

Italy and Spain used an acellular vaccine for infants and children against pertussis. Meanwhile, Iran and Egypt use a whole-cell vaccine. Taking into consideration the low number of deaths in Iran and Egypt compared to Italy and Spain, we could hypothesize that the whole-cell pertussis vaccine could have a cross-immunity against COVID-19. Of note, Pakistan, where the whole-cell pertussis vaccine is included in its routine vaccination schedule also reported a relatively high number of COVID-19 cases (total 277,402) but low number of deaths (total 5,924) [3 Available at: https://www.worldometers.info/coronavirus/]. This observation calls for further research of the possible protective effect of the whole-cell pertussis vaccine against COVID-19; especially that the pertussis vaccine has a weaning protective effect which could explain the lower number of COVID-19 cases before 18 years of age [14Schwartz KL, Kwong JC, Deeks SL, et al. Effectiveness of pertussis vaccination and duration of immunity. CMAJ 2016; 188(16): E399-406.
[http://dx.doi.org/10.1503/cmaj.160193] [PMID: 27672225] ].

Reviewing the vaccination schedules of Italy, Spain, Iran and Egypt, it is noted that all 4 countries include 2 doses of measles vaccine in their obligatory vaccination schedules - thus the measles vaccine does not correlate with any protective effect against COVID-19.

Recently, it was suggested that prior immunity to influenza virus could raise immunity against COVID-19. This hypothesis is supported by the immunity for both viruses, and by the previous studies showing cross reactivity of immunity between influenza and coronavirus due to the similarity in their genetic structures [15Salem ML, El-Hennawy D. The possible beneficial adjuvant effect of influenza vaccine to minimize the severity of COVID-19. Med Hypotheses 2020; 140109752
[http://dx.doi.org/10.1016/j.mehy.2020.109752] [PMID: 32361099] ]. Both Italy and Spain include seasonal influenza vaccine in their vaccination schedules for elderly people (>65 years old) and for patients with chronic diseases like diabetes mellitus and bronchial asthma [4WHO vaccine-preventable diseases: monitoring system 2019 . Available at: https:// apps.who.int/immunization_monitoring/ global summary/countries?countrycriteria%5Bcountry%5D%5B%5D=IRN&commit=OK, 5OECD Data. Influenza vaccination rates Available at: https://data. oecd.org/healthcare/influenza-vaccination-rates.htm]. The Iranian and Egyptian health authorities recommend seasonal influenza vaccine for elderly people and healthcare workers; however the vaccine is not included in the obligatory vaccination schedules [4WHO vaccine-preventable diseases: monitoring system 2019 . Available at: https:// apps.who.int/immunization_monitoring/ global summary/countries?countrycriteria%5Bcountry%5D%5B%5D=IRN&commit=OK]. Although Iran had more confirmed cases of COVID-19 than Italy, the rate of mortality was much lower compared with Italy and Spain. Of note, the number of cases and deaths due to COVID-19 according to the number of general populations in Iran and Egypt is much lower compared with number of cases and deaths in Italy and Spain [3 Available at: https://www.worldometers.info/coronavirus/, 4WHO vaccine-preventable diseases: monitoring system 2019 . Available at: https:// apps.who.int/immunization_monitoring/ global summary/countries?countrycriteria%5Bcountry%5D%5B%5D=IRN&commit=OK]. These comparative results could exclude that the seasonal influenza vaccine may be protective again COVID-19 or is effective for declining the severity among the cases.

Undoubtedly, this ecological study is important being the only raising hypothesis, thus new analytical studies are warranted to confirm the findings [16Susser M. The logic in ecological: I. The logic of analysis. Am J Public Health 1994; 84(5): 825-9.
[http://dx.doi.org/10.2105/AJPH.84.5.825] [PMID: 8179056] ]. The correlation between the vaccination schedules and the number of COVID-19 cases or deaths may not be enough for demonstrating a clear causation, as the data for subgroup analyses is not available yet.

In conclusion, the live attenuated oral poliomyelitis vaccine may potentially explain the relatively low number of cases and deaths due to COVID-19 in some countries, particularly countries from WHO Eastern Mediterranean Region. The whole-cell pertussis vaccine could also offer a protective effect against COVID-19, mainly for youths. Further research is warranted to identify the main reasons for the lower number of COVID-19 cases and deaths in certain countries in order to control the outbreak of COVID-19.