Measles, mumps and rubella vaccine and heterologous immunity: a way out of the COVID-19 crisis?

Abstract

Heterologous immunity is a well-known concept in immunology wherein prior exposure to an antigen confers cross-protection against an unrelated antigen. With the surge in global COVID-19 cases, there has been significant research into the application of vaccine-induced heterologous immunity associated with measles, mumps and rubella (MMR) vaccine, Bacillus Calmette-Guérin vaccine, oral polio vaccine, and hepatitis A vaccine in curbing the worst outcomes of COVID-19 infection. Despite having specific vaccines against COVID-19, it is worthwhile exploring the application of available vaccines in the prevention of severe disease until the vaccines reach all sections of the population across the globe. In this article, we aim to outline the concept of heterologous immunity and its relevance in context to MMR vaccine and COVID-19.

INTRODUCTION

Heterologous immunity refers to the induction of an immune response to an antigen upon previous exposure to an unrelated antigen. It is brought about by modulation of both innate immune response (referred to as ‘trained immunity’) and by alteration in B-cell or T-cell responses [1,2]. Heterologous immunity and its implications, with regard to human vaccination, has long been a subject of research [2]. In the wake of the COVID-19 pandemic, there has been renewed interest in heterologous immunity conferred by vaccines. Epidemiological observations in the COVID-19 era [3-6] suggest that vaccine-induced heterologous immunity could prove to be effective in preventing infection by SARS-CoV-2 or, at the very least, preventing severe disease.

Several vaccines, such as measles, mumps and rubella (MMR) vaccine, Bacillus Calmette-Guérin (BCG) vaccine, oral polio vaccine (OPV), diphtheria, pertussis and tetanus, and hepatitis A vaccines, have been observed to exert an immunological effect over and above their protection against specific pathogen targets [7,8], with BCG and MMR emerging as the most widely studied and validated vaccines pertaining to non-specific immune responses. Even though vaccines are now available against COVID-19, they are gradually being rolled out and percolating the masses, leaving the unvaccinated individuals susceptible to infection. Hence, it is worthwhile exploring the concept of heterologous immunity and the possible impact of MMR vaccination against the worst sequelae of COVID-19 infection.

By means of this review, we attempt to explore the understanding of vaccine-induced heterologous immunity, particularly due to the MMR vaccine, and its implications in curbing the disease-related morbidity and mortality. We have chosen the MMR vaccine as the most promising contender in this regard as MMR viruses share homologous amino acid sequences with SARS-CoV-2, and because the MMR vaccine or other measles rubella-containing vaccines (MRCVs) are a part of the immunisation programmes in many countries and hence, readily available for use.

OBJECTIVE AND METHODS

This article was written with a view to provide a comprehensive appraisal of the data available thus far on the subject of COVID-19 prevention by heterologous immunity induction through administration of MRCVs.

A Medline search updated on 10 October 2021, with search terms ‘COVID-19 AND MMR vaccine’ and filters humans, clinical trials, randomised control trial, meta-analysis, systematic review and all children (0-18 years), yielded 59 results. A simultaneous Cochrane library search yielded five trials out of which three were relevant to our study. Finally, a search on ‘heterologous immunity AND Measles’, with the limits humans, clinical trials, randomised control trial, meta-analysis and systematic review, yielded 54 citations on Medline, and 4 reviews and 674 trials on Cochrane library. Reviews and trials with relevance to heterologous immunity in context to MMR vaccine and MRCVs were taken into account in writing this review. Articles with incomplete data were excluded from this review. The search was carried out independently by two of the authors (JS and MN) and reviewed by the third (SG) so as to increase the sensitivity of data acquisition.

HETEROLOGOUS IMMUNITY: WHAT DO WE KNOW SO FAR?

Immune responses to pathogens can sometimes be altered by previous exposure to antigens, and while these heterologous responses are possibly less effective as compared to specific immune responses to homologous antigens, they can significantly alter the course of infection in a host [9]. One of the most practical implications of this is the phenomenon of heterologous immunity associated with live vaccines [10]. BCG vaccine; MMR vaccine; OPV; and hepatitis A vaccine have been associated with cross-reactivity against other pathogens and partial protection or a stronger immune response against them.

Studies conducted on children in developing countries have concluded that there was a benefit in all-cause mortality and infant mortality after measles vaccination which was over and above that which could be explained by preventing measles-related mortality alone. There are several similarly comparable studies in various population regions that have demonstrated a promising impact of MRCVs on reducing overall childhood mortality and infection-related hospitalisation [11-20].

While the durability of these immune responses over prolonged periods is still a subject under study, it is certain that these effects are maximum during the initial few weeks to months following vaccination. However, one study conducted in Spain showed a significantly lower hospitalisation rate due to respiratory illness not attributable to tuberculosis in BCG-vaccinated children compared to non-BCG-vaccinated children for all age groups [19]. These results are promising as they stipulate persistence of heterologous immune response to over a decade. However, comparable studies based on measles-containing vaccine (MCV) have not yet been conducted. A review by Goodridge et al. [21] concluded that the positive heterologous responses to vaccines can be used to ‘superboost’ the immune system during periods of extreme susceptibility to infections, such as neonatal life and infancy, and contribute to overall improvement of health indices.

In context to COVID-19, a study conducted by Qiu et al. [22], involving 25 paediatric COVID-19-infected cases, found that the group of children <2 years recovered approximately 6 days earlier than the older groups, and had significantly elevated lymphocyte counts upon recovery as compared to the older age group who reported no change in lymphocyte counts or even, lymphocytopenia. This strong immune response in the younger age group was postulated to be due to the frequent immunisations received by the <2 years age group.

MMR VACCINATION: A WAY OUT OF THE COVID-19 CRISIS?

The association of exposure to MMR vaccine and other MRCVs with better outcomes to COVID-19 infection has been a subject of active research since the emergence of the pandemic. The application of MRCVs in context to COVID-19 extends beyond the induction of trained innate immune responses. Molecular analysis of amino acid sequences in routinely administered childhood vaccines revealed homologous sequences between spike (S) glycoprotein of the SARSCoV-2 virus and the fusion (F1) glycoprotein of measles virus, as well as with the envelope (E1) glycoprotein of the rubella virus [23,24]. These short sequences appeared to possess an epitope property, meaning that individuals who have received the MRCVs could potentially mount an immune response against COVID-19 infection as well. According to a review by Saad and Elsalamony [25], MCV may provide bystander immunity against COVID-19, in addition to the cross-protection offered due to the structural homology between the viruses.

Moreover, MMR or similar MRCVs are a part of the national immunisation programmes of several countries and therefore are easily and readily available for use. According to the WHO data, 172 member states have a 2-dose measles immunisation policy, leading to a global coverage of 71% as of 2019 and 173 member states have rubella vaccine in their immunisation programmes [26]. This is in contrast to the OPV which is currently not licensed for use in high income countries, such as USA, leading to logistical difficulties for their use [27].

While there are no randomised controlled trials as of now regarding the impact of MRCVs on COVID-19 infection, several epidemiological and retrospective observational studies have been conducted along the same hypothesis. According to published global data, there is a clearly demarcated pivot point on the epidemic curve around the age of 50 years. This is thought to be related with the introduction of mass vaccination with MRCVs, nearly five decades ago. Countries with an aggressive immunisation policy have revealed lower infection and mortality rates due to COVID-19. In USA, the low infection rates in children above 1 year of age correspond to the Centres for Disease Control and Prevention immunisation policy of administering the first MMR dose between 12 and 15 months, followed by a booster at 4-6 years [28]. These findings can be extrapolated to the Indian scenario as well. A study conducted by Gohil et al. [29] on 192 healthy college students (age 18-23 years) found MMR seroprevalence to be 91% for measles, 97% for mumps and 88% for rubella, which goes in accordance with the observation of reduced incidence of infection and milder disease course in the younger population [29].

In a prospective observational trial [30], 255 participants were vaccinated with MMR vaccine at the start of the pandemic and followed up for development of COVID-19. Only 36 of all recruited participants were found to present with COVID-19, all of them showing a mild course of disease, despite comorbidities, such a diabetes and hypertension, which are usually associated with severe disease in COVID-19 [30]. In another descriptive observational study based on an anonymous survey involving primary care physicians in Madrid, it was found that 67.2% of the physicians who recalled being immunised with MMR vaccine reported a mild course of disease. None of those who was hospitalised could remember being exposed to MMR vaccine or being immunised against any of the viruses contained in the vaccine [31].

Franklin et al. [32] found that patients with severe illness had increased levels of rubella immunoglobulin G (IgG) (161.9 + 147.6 IU/ml) compared to patients with a moderate severity of disease (74.5 + 57.7 IU/ml). This seems to point towards the fact that patients are responding with increased rubella antibody titres to SARS-CoV-2 infection, furthering our assumption about heterologous immune responses. A study by Gold et al. [33] found an inverse correlation between mumps IgG and COVID-19 severity. Highest mumps antibody titres were found in those who had asymptomatic COVID-19 infection, whereas severe cases had very low levels of mumps IgG. They also noted that COVID-19 case prevalence was up to seven times lower in young children [33].

A case-control study conducted on healthcare workers during a measles outbreak, for which MMR vaccine was administered, demonstrated that there is a protective effect of MMR vaccination against COVID-19 in males, but not in females [34]. In a comparative analysis between COVID-19-recovered individuals and age-matched healthy controls, measles-specific IgG titres were found to be significantly higher in the patient group, suggesting B-cell heterologous responses between the two viruses. This could potentially be reverse engineered to induce a protective response against COVID-19 by means of measles vaccination [35].

In a systematic analysis of the immunisation records of the COVID-19-infected population based in the United Stated, Pawlowski et al. [36] found a diminution of infection rates in individuals recently vaccinated with MMR, a difference that held up despite matching for demographic parameters and comorbidities. A real-time case-control analysis conducted in Pune, India, during the peak of the pandemic also showed a reduced incidence of infection in children vaccinated with MCVs, along with a reduced frequency of symptoms in those infected with COVID-19 [37].

Another promising exploratory analysis published by Mysore et al. [38] not only suggested a T-cell receptor homology between MMR vaccine and COVID-19, but also postulated that prior vaccination with MMR produced an enhanced T-cell response to COVID-19 vaccination. This further goes on to show the application of MRCVs not only in tiding over the pandemic crisis, but in building a robust defence against SARS-CoV-2 in a post-vaccine era.

An epidemiological survey written by Ogimi et al. [39] also found an association between MCV coverage and fewer reported death rates due to COVID-19, but this association did not hold when the data were adjusted for the Healthcare Access and Quality Index (HAQI) [39]. However, this was a national level analysis and therefore does not adequately reflect individual exposures and outcomes.

While all these studies appear promising, it is yet to be seen whether the protection offered by the antibodies acquired after exposure to MRCVs have a neutralising effect on COVID-19 or not. A study conducted by Kandeil et al. [40] found that none of the childhood vaccines, including MMR vaccine, were capable of inducing cross-reactive neutralising antibodies against SARS-CoV-2 in Bagg and Albino (BALB/c) mice up to 7 weeks post-vaccination. They concluded that the disease-modulating effect of childhood vaccines is not antibody-mediated [40].

In addition, there are studies which show that cross-reactive B-cell and T-cell responses create an unfavourable environment for immune responses to COVID-19 due to the phenomenon of antibody-dependent enhancement, which is commonly observed with dengue viral infections [41]. It is expected that an early, potent response with neutralising antibodies should be able to clear the infection earlier. However, in practice, there is an unexpected association between early immune response and severe COVID-19 infection [42]. This is consistent with the pattern observed by Zhang et al. [43] in context to SARS-CoV-1 infection, which showed a peak by the 15th day in neutralising antibody levels among fatal cases, whereas those in convalescent cases were still on the rise. A study conducted by Yonker et al. [44], who followed up a cohort of 192 SARS-CoV-2-infected children, including 18 children who met the criteria for multisystem inflammatory syndrome in children (MIS-C), found that IgM and IgG against the SARS-CoV-2 spike protein were increased in severe MIS-C. Therefore, if exposure to MMR or other vaccines containing the same antigen does induce a heterologous immune response in the form of enhanced memory T-cell activation and subsequent production of neutralising antibodies, children should be expected to have a worse disease outcome with a larger portion of infected cases gravitating towards the moderate to severe disease presentations. However, that is not the case as observed by epidemiological studies.

The answer to the unique pattern of immune response observed in children might be explained by Carsetti et al. [45]. Their study finds an early polyclonal B-cell response in children which is not mirrored in adults with severe disease due to depleted B-cell compartment. The neonatal B-cells, activated B-cells and IgA plasmablasts have the secondary, but important, function of producing IL-10, which is a potent anti-inflammatory molecule. Therefore, it may be concluded that in children the immune system can exert protection and simultaneously and also prevent or reduce immune-mediated lung damage. Nonetheless, it is apparent that exposure to live vaccines and MMR vaccine, in particular (due to the structural similarity of the viral antigens in the vaccine with COVID-19 virus), does appear to have a beneficial disease-modulating impact on COVID-19 infection. As per Fidel and Noverr [46], receipt of the MMR vaccine might lead to reduced severity of COVID-19 infections. At the very least, it will enhance the immunity against the target viruses, without many side effects. Thus, it may prove to be a low-risk, high-reward measure in dealing with the COVID 19 crisis.

IMPLICATIONS AND SCOPE OF FURTHER RESEARCH

The immune responses to COVID-19 infection are variable and complex with differences in immune behaviour between children and adults. The role of MMR vaccine in modifying the disease severity of COVID-19 seems promising but requires high-quality randomised controlled trials as proof. While there is a sound evidence base to prove an association of reduced disease severity in MMR vaccinated individuals, it is not sufficient to prove causality. Moreover, it cannot be denied that epidemiological studies have a low quality evidence level and are prone to the risk of bias. We have summarised the findings of this article in Table 1.

Table 1.

Summary of the data available on the induction of heterologous immunity against COVID-19 by MRCVs.

Authors	Study population	Type of study	Result
Sidiq et al. [23]	Children	Hypothesis	30 amino acid sequence homologies between measles, rubella and SARS-CoV-2 proteins could lead to cross-protection to COVID-19 after MMR immunisation
Anbarasu et al. [24]	Children	Hypothesis	Induction of NK cells and IFNs after MMR immunisation could boost natural immunity against COVID-19
Saad and Elsalamony [25]	All population	Hypothesis	Measles immunisation could lead to milder COVID-19 infections by generation of heterologous immunity
Ashford et al. [28]	All population	Hypothesis	MMR vaccination may provide strong protection to COVID-19 particularly in the elderly and those with comorbidities
Larenas-Linnemann and Rodríguez-Monroy [30]	All population	Clinical trial	Out of 255 subjects vaccinated with MMR vaccine, only 36 participants developed COVID-19 and had a mild course of disease
López-Martin I et al. [31]	Primary care physicians	Observational	67.92% of the physicians infected with COVID-19 who had received MMR vaccine presented with mild symptoms and did not require hospitalisation
Gold et al. [33]	All population	Observational	There was a significant inverse correlation between mumps titres in MMR vaccinated subjects and COVID-19 severity
Lundberg et al. [34]	Healthcare workers	Case control	Protective effect of MMR vaccination against COVID-19 found in males
Hassani et al. [35]	COVID 19-infected patients	Case control	Measles vaccination triggers production of cross-reactive antibodies against COVID-19
Pawlowski et al. [36]	All population	Observational	MMR vaccination has a strong negative correlation with COVID-19 infection rates
Gujar et al. [37]	Children	Case control	MCVs have a strong protective effect in paediatric age group against COVID-19 infection
Mysore et al. [38]	All population	Observational	High correlation between T-cell responses to COVID-19 and MMR vaccination in COVID-19 recovered and immunised individuals
Ogimi et al. [39]	All population	Ecological	Association between MCV coverage and fewer reported COVID-19-related deaths which did not hold when adjusted for HAQI
Kandeil et al. [40]	Mice	Animal trial	No cross-reactive antibodies against COVID-19 seen in MMR vaccinated mice
Fidel et al. [46]	All population	Hypothesis	MMR vaccination through induction of trained immunity could provide a low-risk, high-reward protection against COVID-19

HAQI, Healthcare Access and Quality Index; MCVs, measles-containing vaccines; MMR, measles, mumps and rubella.

However, with the grave risks posed by the COVID-19 crisis, as well as the burden on the health infrastructure, it appears worthwhile to intensify immunisation policies and use the non-specific effects of vaccines to tide over the pandemic situation and prevent further outbreaks. With accelerated vaccine development for COVID-19, vaccine-vigilance and post-marketing surveillance become all the more important, as well as the ethical concerns of ensuring equitable distribution of specific vaccines globally. In addition, with the wide variety of COVID-19 vaccines with variable efficacy available today, there is little harm in exploring the use of MMR vaccine in prolonging or boosting the immune response against SARS-CoV-2. Furthermore, SARS-CoV-2 has mutated several times since its emergence in 2019. Keeping the possibility of future emergence of new strains and resultant pandemics in mind, it may be a rewarding exercise to utilise the existing vaccines, such as MMR, in combination with specific COVID vaccines, to prevent the more serious infections and infection-related mortality. We propose this strategy as a short-term measure, especially for resource-limited countries that rely on import of vaccines from outside, and hence have a shortage of supply in comparison to demand.

Secondly, the pandemic has altered the health-seeking behaviour of people, with the result of interruption in routine childhood immunisation. This could potentially lead to outbreaks of childhood communicable diseases, and therefore, it becomes all the more necessary to focus on delivering the minimum vaccines to children. The association of MMR vaccination and disease modulation of COVID-19 infection is an added impetus to the immunisation programme, especially in middle- and low-income countries where infections are still a leading cause of under-five mortality.

Additionally, there are several questions that need to be answered in this context. Are there differences in disease patterns, antibody responses and COVID-19-associated morbidity between children of the same age who are vaccinated and unvaccinated? Is there any difference in immune response between children who receive two doses of MMR vaccine and those who receive a single dose, and if so, is there a differential response related to the age at first exposure of the vaccine? While we know that the heterologous immunity is most active in the initial few months after vaccination, the question still stands as to when administration of MMR vaccine may prove most fruitful in preventing the most adverse sequelae of COVID-19 infection. Besides providing insight into COVID-19-associated immunity, the enigma of MMR vaccination and heterologous immunity is a fertile ground for research in immunology and furthering our understanding of the non-specific effects of vaccines and their impact on modification of unrelated infections.

CONCLUSION

Although being resource-intensive and tough to perform, the need of the hour is high-quality randomised controlled trials to explore the impact of MMR vaccination on COVID-19 infection, in terms of both natural history of disease and subsequent antibody response. The use of existing childhood vaccines, such as MMR, in combating the surge of COVID-19-related morbidity and mortality, is potentially a low-risk, high-yield measure for all populations until the pandemic curve shows a permanent decline.

CONFLICT OF INTEREST

The authors report no conflict of interest.

FUNDING

None.

ETHICAL APPROVAL

No ethical approval was required.