Our study is the only study that was performed on the effect of rubella IGG on severity of COVID-19 disease. This study showed that high IGG levels can play an important role in the development of milder COVID-19.
Having COVID-19 vaccination history is not associated with rubella IGG level. However, existence of COVID-vaccination has positive accumulating effect with rubella IGG titer on reducing the severity of the COVID-19 disease. All patients reported as far as they remember, had no history of Measles, Mumps, and Rubella (MMR) vaccination recently.
Routinely, MMR vaccination includes children 12 and 18 months and also if necessary for women who are planning to become pregnant in Iran. Furthermore, a national measles–rubella vaccination campaign was initiated in December 2003 in Iran, targeting individuals aged 5–25 years (people under 44 years old at the end of 2021((15). We compared the median of rubella IGG titers in the two age groups (> 43 and ≤ 43 years old) and there was a huge difference in IGG rubella level between the two age groups (about 100 units). In addition, an interaction between the age group under 44 years and IGG rubella titer was detected in development of milder COVID-19. There was a positive interaction between birth year (quantitative) variable and rubella IGG on COVID-19 severity too. During aging, comorbidities with chronic diseases and, the immune system changes increase the chance of COVID- 19 disease severity(25), Therefore, the modification between the year of birth and the IGG rubella titer on the severity of the disease can be justified.
Some studies have reported that the MMR vaccine may protect against or reduce the severity, hospitalization, or mortality of coronavirus disease 2019 infection (1, 5–10). This theory was introduced by Gold et al(2020), after observing that recent countries with large-scale MMR vaccination are associated with the fewest COVID-19 deaths (14)
SARS-CoV-2 is an encapsulated, single-stranded RNA virus, belonging to the genus Betacoronavirus, subgenus Sarbecovirus, from the family of Coronaviridae. Sharing approximately 80% similarity with SARS-CoV-1 and 96% similarity with bat coronavirus, the genome of SARS-CoV-2 encodes 4 structural proteins, including the spike (S), envelope (E), membrane (M), and nucleocapsid (NP), besides other non-structural proteins(26).
MMR vaccines consist of attenuated enveloped ssRNA viruses that have glycoprotein spikes, similar to SARS-CoV2. There is 32%, 31% and 33% homology between the spike amino acid sequences of measles, mumps and rubella, respectively, with that of the SARS-CoV2(9)
Researchers have proposed this theory that preexisting immunity against COVID-19 may be due to the cross-reactivity with other antigens, for example the ones resulting from previous immunizations(27).
It is a theory that one or more of the MMR components may be structurally similar to SARS-CoV epitopes recognized by the immune system and may contribute to cross-immunity(16). In some of studies, measles vaccine has been introduced as an important and effective factor in this cross-reactivity (5, 17, 18).
Hassani and colleagues(2021) reported that measles vaccination trigger those B cells cross-reactive with SARS-CoV-2 antigens leading to production of increased levels of measles-specific IgG(17). Epithelial cells also carry Fc receptor on their surface that can interact with IgG and transport them for intracellular disruption of viral replication (5, 18)
In a homologous study by Marakasova, and Baranovaa, a similarity between the receptor binding domain (RBD) of the surface glycoprotein of SARS-CoV-2 causing coronavirus disease 2019 and the measles fusion glycoprotein was found too(19) .
But in contrast, analysis of Klimczak et al(2021) demonstrated that there was a statistically significant similarity between the distributions of base substitution densities in rubella and in each of three filtered SARS-CoV-2 Mutation Annotation Formats (MAFs) as well as a similarity in several prevailing types of base substitutions(20).
According to Anbarasua and colegues, even though COVID 19 is impacting all aspects of life, the interesting scenario is slight symptoms in the young; mainly in children under 10 years of age, of note this age group is the most susceptible to infectious diseases(1) So, it seems the extensive pediatric MMR vaccination schedule is effective in their safety and widespread vaccination is effective in their safety against COVID-19(1). they agreed that mass neonatal vaccination with MMR vaccines globally might result in innate immune responses leading to induction of interferons (IFN)s and NK cells, thus offering non-specific immunity against COVID- 19 virus in children(1, 17). In confirmation of this theory, it was reported that milder symptoms observed in the 955 sailors on the USS Roosevelt navy who tested positive for COVID-19 (only one hospitalization) may have been due to the fact that all US navy recruits were compulsorily vaccinated with MMR(11).
However, a limited number of researchers disagreed with cross-reactivity effect in live vaccines including MMR and BCG and they have emphasized that some countries like Iran and Latin American countries, e.g., Chile, Argentina, and Ecuador, maintain 90% vaccine coverage, which started BCG vaccination in 1985 or even earlier, still have high mortality from COVID-19 (21, 22). Also since the other set of live vaccines (BCG, polio, rotavirus, and chickenpox) also are administered at less than 1 year of age, this could result in a cumulative effect(23). In confirmation of the lack of MMR vaccination effect in the prevention of more severe COVID − 19 diseases, Lundberg and colleagues (in a study on health care workers (2021) proposed that MMR-vaccination up to 2.5 years prior affords no considerable protective effect against COVID-19 infection. However, in sex-stratified analyses, recently MMR-vaccinated men had 57% vaccine effectiveness at preventing symptomatic disease (P = 0.006) (28).
In our study, analyses was based on the rubella IGG titer (not MMR vaccination), and its measurement was conducted in the first 24 to 48 hours of hospitalization. Although patients who are hospitalized due to COVID-19 show relatively more severe cases or underlying diseases, hospitalized patients also have different groups in disease severity.
The high level of rubella IGG titers in the age group under 44 years (individuals included in the 2003 national MR vaccination) and the presence of strong interaction between the individuals under 44 years and the rubella IGG level on the milder of the COVID-19 disease, the possibility of vaccine cumulative effect (including mumps, polio, BCG, etc.) could be rejected.
On the other hand, the increase in the rubella IGG titer is not always due to vaccination, natural circulation of the virus as a natural booster has played a major role in increasing antibodies(15) and it is well known that vaccine-induced immunity is lower than that resulting from natural exposure to the wild virus, and there are indications that vaccine-induced rubella immunity declines over time among those who received a single dose of vaccine(29).
One of the limitations of the present study was the low sample size. It is recommended to perform predictive analysis and diagnostic accuracy in studies with larger sample size (above 100 cases).