Although only limited evidence has been observed in support of COVID-19 prevention by non-specific effects of the BCG vaccine, this does not exclude the possibility of the vaccine's non-specific preventive effects against COVID-19. On the other hand, there is also a possibility that other live attenuated vaccines could provide non-specific effects against COVID-19 as well, based on the fact that children are subject to vaccine programmes and are less susceptible to COVID-19 infection. This blog post is going to introduce the other three candidate live attenuated vaccines suggested by scientists: oral poliovirus vaccine (OPV), measles vaccine, and MMR (measles, mumps, rubella) vaccine. I would like to share with you the hypothesis on why and how these three vaccines may also provide protection against COVID-19.
Oral poliovirus vaccine (OPV)
OPV is a live attenuated vaccine that helps to prevent the paralysis caused by the poliovirus infection to the central nervous system. In seven randomized controlled trials from 2002 to 2014 in Guinea-Bissau, a country which did not have previous polio infections, the all-cause mortality decreased 19% since a national immunization campaign with OPV was launched.1 This indicates that OPV has beneficial non-specific effects. In fact, early clinical studies showed that OPV reduced the amount of other viruses that could be isolated from the immunized group of children, when compared with placebo group.2,3 Most importantly, clinical studies performed from 1969 to 1971 showed that OPV was effective in preventing influenza and the concomitant acute respiratory disease, with a maximum of 3.1-fold morbidity rate reduction.4 This indicates that OPV can stimulate the innate immunity* to protect against respiratory infection, thus suggesting that the vaccine may be able to provide temporary protection against COVID-19, a respiratory infection disease.2
Compared to the BCG vaccine, OPV has some important advantages: the BCG vaccine is a weakened bacteria, while poliovirus and coronavirus are both positive-strand RNA viruses. It is likely that poliovirus and coronavirus may induce and be affected by common innate immunity mechanisms.2 Therefore OPV is more likely to confer protective effects against COVID-19 than the BCG vaccine.
Moreover, since OPV has a stronger safety record, the risk of complications due to OPV is extremely low. Vaccine-associated paralytic polio develops in 1 per 3 million vaccine doses, mostly in immunocompromised children. On the other hand, up to 1% of BCG vaccine immunized children need medical attention due to some adverse reactions.2
Furthermore, OPV has more than one serotype, so the vaccines could be used sequentially to prolong protection.2.4 The lower cost, ease of administration, availability, and the ease to scale up production are other advantages. More than a billion doses of OPV are produced and used in over 140 countries per year, while the supply of BCG vaccine is more limited. Therefore a relatively much smaller fraction of OPV should be enough for clinical trials to test its non-specific effects against COVID-19, without needing to fear that its supply to current polio eradication campaigns in developing countries will be limited.2 By contrast, the possible use of the BCG vaccine for COVID-19 has already given rise to concerns over the availability of the vaccine as immunotherapy to patients with bladder cancer, due to its limited availability.
Although OPV seems promising in its ability to protect against COVID-19 and many researchers have suggested the testing of the vaccine,2 no clinical trial has yet been launched to investigate this. Not even a registration of a relevant trial is seen in any public clinical trials registry platform.
Measles vaccine
According to the World Health Organization, measles is a highly contagious and deadly disease caused by a virus in the paramyxovirus family. It infects the respiratory tract, then spreads throughout the body. In 2018, it caused more than 140,000 deaths, mainly in children under 5, despite the availability of a safe and effective vaccine. Routine measles vaccination for children, combined with mass immunization campaigns in countries with high case rates and death rates, are key public health strategies to reduce global measles deaths.5
The measles vaccine has long been observed in association with pronounced non-specific protective effects against contagious diseases.6,7 When the measles vaccine was introduced in 7 African countries, the overall mortality in children of those countries declined by 30% to 86%, a reduction far larger than anticipation based on the protection against deaths caused by measles alone.6 A random controlled trial found that the measles vaccine was associated with a 30% reduction in overall mortality in children. Among these, only 4% could be explained by prevention of measles infection.7
The vaccine is an efficient, live attenuated, replicating virus. It has been safely administered to 2 billion children over the last 40 years, affording life-long protection after a single dose.8 These advantages made the vaccine a popular vaccine vector candidate to be genetically engineered. In the last few years, scientists have genetically engineered the measles vaccine and tested the result's protection efficiency against two coronavirus-caused diseases: SARS (Severe Acute Respiratory Syndrome) and MERS (Middle-East Respiratory Syndrome).
In 2014, a recombinant measles vaccine which incorporates and expresses the spike protein (a surface protein mediates attachment of virus) of SARS was constructed.9 It was found that the live-attenuated recombinant measles vaccine could induce neutralizing antibodies, and that it protected immunized mice from infection by SARS-CoV.9 In 2018, two live-attenuated recombinant measles virus vaccines, either expressing S protein or N protein (structural protein on the surface of virus) of MERS-CoV, were found to induce a robust humoral and cellular immunity response against MERS-S mediating protection in the mouse model.10
Based on the above experimental results, a genetically-engineered measles vaccine carrying the S or the N protein pf SARS-CoV-2 may be an option to provide protective effects against COVID-19.
MMR (measles, mumps and rubella) vaccine
The MMR vaccine is a combined live attenuated vaccine that helps to prevent measles, mumps and rubella. Research studies of two scientists, Dr Paul Fidel and Prof. Mairi Noverr, in the USA, found that the combined vaccine could induce myeloid-derived suppressor cells (MDSCs). The induction of these cells from bone marrow reduced inflammation and mortality in mouse models.11 Moreover, previous experimental studies showed that MDSCs inhibit septic inflammation.12 Based on the above findings, the two scientists suggest that the combined vaccine could induce MDSCs in COVID-19 patients and help them to fight the lung inflammation and sepsis which associated with the most serious cases of the disease.11
Adults who received the MMR vaccine as a child will likely still have antibodies against the measles, mumps and rubella viruses, but are unlikely to still have MDSCs, as these cells are not life-long cells. This means they would require a second time injection to reinitiate the MDSCs and obtain the potential benefits against COVID-19.
Besides the experimental evidence, the report from Dr Paul Fidel and Prof. Mairi Noverr cited a recent event that support their hypothesis. The 955 sailors on the U.S.S. Roosevelt who tested positive for COVID-19 had milder symptoms, except for one hospitalization. They suggested that this may have been a consequence of the MMR vaccinations given to all U.S. Navy recruits. However, this may also be the fact that they are young and stronger.11
By genetic data analysis, a team lead by Prof. Robin Franklin at Cambridge University have identified a 29% amino acid sequence homology between the Macro (ADP-ribose-1-phosphatase) domains of SARS-CoV-2 and the rubella virus which is used the MMR vaccine. This provides further preliminary evidence that the MMR vaccine might provide protection against COVID-19.13
The MMR vaccine is highly safe. The vaccination of immunocompetent individuals has no contra-indications. A clinical trial of the MMR vaccine in high-risk healthcare workers in New Orleans has been proposed by Dr Paul Fidel and Prof. Mairi Noverr. They have also been awarded a grant to compare the MMR and BCG vaccines in a primate model of COVID-19.11
Although no existing live attenuated vaccine, nor specific vaccine has yet found to be effective in preventing COVID-19, the existing vaccines that induce non-specific protection do have theoretical advantages over a vaccine specific to SARS-CoV-2. If proven to be effective against COVID-19, there is a higher chance the existing vaccine will still able to confer protection by its broad protection effects even when SARS-CoV-2 undergoes mutation. This is because the vaccine's non-specific effect works by boosting a person's immune response in general. By contrast, a vaccine specific to SARS-CoV-2 has a higher chance of losing its efficacy if the virus mutates, leading to antigenic drift.2
* Innate immunity: Live attenuated vaccines provide non-specific protection against lethal infections unrelated to the target pathogen by inducing "trained" non-specific innate immune cells. This improves a host's responses against subsequent infections. This type of non-specific immune response is the first line of defence against infection and is called the innate immune response. Recent reports show that COVID-19 may suppress innate immune responses.14 Therefore, stimulation by live attenuated vaccines could increase resistance to infection by SARS-CoV-2, the causal virus.
References
1. A. Andersen, A.B. Fisker, A. Rodrigues, et al. National immunization campaigns with oral polio vaccine reduce all-cause mortality: A natural experiment within seven randomized trials.Front. Public Health, 2018 Feb 2, 6: 13.
2. K. Chumakov, C.S. Benn, P. Aaby, et al. Can existing live vaccines prevent COVID-19. Science, 2020, vol. 368, Issue 6496, 1187-1188.
3. E. Seppälä, H. Viskari, S. Hoppu, et al. Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media. Vaccine, 2011, 29, 8615-8618.
4. M.K. Voroshilova. Potential use of nonpathogenic enteroviruses for control of human disease. Prog. Med. Virol., 1989, 36, 191-202.
5. https://www.who.int/news-room/fact-sheets/detail/measles
6. P. Aaby, B. Samb, F. Simondon, et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ, 1995 Aug 19, 311(7003): 481-485.
7. P. Aaby and C.S. Benn. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Clin. Microbiol. Infect., 2019 Dec., 25(12):1459-1467.
8. P.N. Frantz, S. Teeravechyan, and F. Tangy. Measles-derived vaccines to prevent emerging viral diseases. Microbes Infect., 2018, 20:493-500.
9. N. Escriou, B. Callendret, V. Lorin, et al. Protection from SARS coronavirus conferred by live measles vaccine expressing the spike glycoprotein. Virology. 2014, 452-453:32-41.
10. B.S. Bodmer, A.H. Fiedler, J.R.H. Hanauer, et al. Live-attenuated bivalent measles virus derived vaccines targeting Middle East respiratory syndrome coronavirus induce robust and multifunctional T cell responses against both viruses in an appropriate mouse model. Virology, 2018, 521:99-107.
11. P.L. Fidel and M.C. Noverr. Could an unrelated live attenuated vaccine serve as a preventive measure to dampen septic inflammation associated with COVID-19 infection? mBio, DOI:10.1128/mBio.00907-20
12. S.K. Esher, P.L. Fidel, M.C. Noverr. Candida/staphylococcal polymicrobial intra-abdominal infection: pathogenesis and perspectives for a novel form of trained innate immunity. J. Fungi (Basel), 2019 Jun; 5(2): 37.
13. R. Franklin, A. Young, B. Neumann, et al. Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19. MedRxiv, doi: https://doi.org/10.1101/2020.04.10.20053207
14. M. Zheng, Y. Gao, G. Wang, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol., 2020 May, 17 (5), 533-535.
Oral poliovirus vaccine (OPV)
OPV is a live attenuated vaccine that helps to prevent the paralysis caused by the poliovirus infection to the central nervous system. In seven randomized controlled trials from 2002 to 2014 in Guinea-Bissau, a country which did not have previous polio infections, the all-cause mortality decreased 19% since a national immunization campaign with OPV was launched.1 This indicates that OPV has beneficial non-specific effects. In fact, early clinical studies showed that OPV reduced the amount of other viruses that could be isolated from the immunized group of children, when compared with placebo group.2,3 Most importantly, clinical studies performed from 1969 to 1971 showed that OPV was effective in preventing influenza and the concomitant acute respiratory disease, with a maximum of 3.1-fold morbidity rate reduction.4 This indicates that OPV can stimulate the innate immunity* to protect against respiratory infection, thus suggesting that the vaccine may be able to provide temporary protection against COVID-19, a respiratory infection disease.2
Compared to the BCG vaccine, OPV has some important advantages: the BCG vaccine is a weakened bacteria, while poliovirus and coronavirus are both positive-strand RNA viruses. It is likely that poliovirus and coronavirus may induce and be affected by common innate immunity mechanisms.2 Therefore OPV is more likely to confer protective effects against COVID-19 than the BCG vaccine.
Moreover, since OPV has a stronger safety record, the risk of complications due to OPV is extremely low. Vaccine-associated paralytic polio develops in 1 per 3 million vaccine doses, mostly in immunocompromised children. On the other hand, up to 1% of BCG vaccine immunized children need medical attention due to some adverse reactions.2
Furthermore, OPV has more than one serotype, so the vaccines could be used sequentially to prolong protection.2.4 The lower cost, ease of administration, availability, and the ease to scale up production are other advantages. More than a billion doses of OPV are produced and used in over 140 countries per year, while the supply of BCG vaccine is more limited. Therefore a relatively much smaller fraction of OPV should be enough for clinical trials to test its non-specific effects against COVID-19, without needing to fear that its supply to current polio eradication campaigns in developing countries will be limited.2 By contrast, the possible use of the BCG vaccine for COVID-19 has already given rise to concerns over the availability of the vaccine as immunotherapy to patients with bladder cancer, due to its limited availability.
Although OPV seems promising in its ability to protect against COVID-19 and many researchers have suggested the testing of the vaccine,2 no clinical trial has yet been launched to investigate this. Not even a registration of a relevant trial is seen in any public clinical trials registry platform.
Measles vaccine
According to the World Health Organization, measles is a highly contagious and deadly disease caused by a virus in the paramyxovirus family. It infects the respiratory tract, then spreads throughout the body. In 2018, it caused more than 140,000 deaths, mainly in children under 5, despite the availability of a safe and effective vaccine. Routine measles vaccination for children, combined with mass immunization campaigns in countries with high case rates and death rates, are key public health strategies to reduce global measles deaths.5
The measles vaccine has long been observed in association with pronounced non-specific protective effects against contagious diseases.6,7 When the measles vaccine was introduced in 7 African countries, the overall mortality in children of those countries declined by 30% to 86%, a reduction far larger than anticipation based on the protection against deaths caused by measles alone.6 A random controlled trial found that the measles vaccine was associated with a 30% reduction in overall mortality in children. Among these, only 4% could be explained by prevention of measles infection.7
The vaccine is an efficient, live attenuated, replicating virus. It has been safely administered to 2 billion children over the last 40 years, affording life-long protection after a single dose.8 These advantages made the vaccine a popular vaccine vector candidate to be genetically engineered. In the last few years, scientists have genetically engineered the measles vaccine and tested the result's protection efficiency against two coronavirus-caused diseases: SARS (Severe Acute Respiratory Syndrome) and MERS (Middle-East Respiratory Syndrome).
In 2014, a recombinant measles vaccine which incorporates and expresses the spike protein (a surface protein mediates attachment of virus) of SARS was constructed.9 It was found that the live-attenuated recombinant measles vaccine could induce neutralizing antibodies, and that it protected immunized mice from infection by SARS-CoV.9 In 2018, two live-attenuated recombinant measles virus vaccines, either expressing S protein or N protein (structural protein on the surface of virus) of MERS-CoV, were found to induce a robust humoral and cellular immunity response against MERS-S mediating protection in the mouse model.10
Based on the above experimental results, a genetically-engineered measles vaccine carrying the S or the N protein pf SARS-CoV-2 may be an option to provide protective effects against COVID-19.
MMR (measles, mumps and rubella) vaccine
The MMR vaccine is a combined live attenuated vaccine that helps to prevent measles, mumps and rubella. Research studies of two scientists, Dr Paul Fidel and Prof. Mairi Noverr, in the USA, found that the combined vaccine could induce myeloid-derived suppressor cells (MDSCs). The induction of these cells from bone marrow reduced inflammation and mortality in mouse models.11 Moreover, previous experimental studies showed that MDSCs inhibit septic inflammation.12 Based on the above findings, the two scientists suggest that the combined vaccine could induce MDSCs in COVID-19 patients and help them to fight the lung inflammation and sepsis which associated with the most serious cases of the disease.11
Adults who received the MMR vaccine as a child will likely still have antibodies against the measles, mumps and rubella viruses, but are unlikely to still have MDSCs, as these cells are not life-long cells. This means they would require a second time injection to reinitiate the MDSCs and obtain the potential benefits against COVID-19.
Besides the experimental evidence, the report from Dr Paul Fidel and Prof. Mairi Noverr cited a recent event that support their hypothesis. The 955 sailors on the U.S.S. Roosevelt who tested positive for COVID-19 had milder symptoms, except for one hospitalization. They suggested that this may have been a consequence of the MMR vaccinations given to all U.S. Navy recruits. However, this may also be the fact that they are young and stronger.11
By genetic data analysis, a team lead by Prof. Robin Franklin at Cambridge University have identified a 29% amino acid sequence homology between the Macro (ADP-ribose-1-phosphatase) domains of SARS-CoV-2 and the rubella virus which is used the MMR vaccine. This provides further preliminary evidence that the MMR vaccine might provide protection against COVID-19.13
The MMR vaccine is highly safe. The vaccination of immunocompetent individuals has no contra-indications. A clinical trial of the MMR vaccine in high-risk healthcare workers in New Orleans has been proposed by Dr Paul Fidel and Prof. Mairi Noverr. They have also been awarded a grant to compare the MMR and BCG vaccines in a primate model of COVID-19.11
Although no existing live attenuated vaccine, nor specific vaccine has yet found to be effective in preventing COVID-19, the existing vaccines that induce non-specific protection do have theoretical advantages over a vaccine specific to SARS-CoV-2. If proven to be effective against COVID-19, there is a higher chance the existing vaccine will still able to confer protection by its broad protection effects even when SARS-CoV-2 undergoes mutation. This is because the vaccine's non-specific effect works by boosting a person's immune response in general. By contrast, a vaccine specific to SARS-CoV-2 has a higher chance of losing its efficacy if the virus mutates, leading to antigenic drift.2
* Innate immunity: Live attenuated vaccines provide non-specific protection against lethal infections unrelated to the target pathogen by inducing "trained" non-specific innate immune cells. This improves a host's responses against subsequent infections. This type of non-specific immune response is the first line of defence against infection and is called the innate immune response. Recent reports show that COVID-19 may suppress innate immune responses.14 Therefore, stimulation by live attenuated vaccines could increase resistance to infection by SARS-CoV-2, the causal virus.
References
1. A. Andersen, A.B. Fisker, A. Rodrigues, et al. National immunization campaigns with oral polio vaccine reduce all-cause mortality: A natural experiment within seven randomized trials.Front. Public Health, 2018 Feb 2, 6: 13.
2. K. Chumakov, C.S. Benn, P. Aaby, et al. Can existing live vaccines prevent COVID-19. Science, 2020, vol. 368, Issue 6496, 1187-1188.
3. E. Seppälä, H. Viskari, S. Hoppu, et al. Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media. Vaccine, 2011, 29, 8615-8618.
4. M.K. Voroshilova. Potential use of nonpathogenic enteroviruses for control of human disease. Prog. Med. Virol., 1989, 36, 191-202.
5. https://www.who.int/news-room/fact-sheets/detail/measles
6. P. Aaby, B. Samb, F. Simondon, et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ, 1995 Aug 19, 311(7003): 481-485.
7. P. Aaby and C.S. Benn. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Clin. Microbiol. Infect., 2019 Dec., 25(12):1459-1467.
8. P.N. Frantz, S. Teeravechyan, and F. Tangy. Measles-derived vaccines to prevent emerging viral diseases. Microbes Infect., 2018, 20:493-500.
9. N. Escriou, B. Callendret, V. Lorin, et al. Protection from SARS coronavirus conferred by live measles vaccine expressing the spike glycoprotein. Virology. 2014, 452-453:32-41.
10. B.S. Bodmer, A.H. Fiedler, J.R.H. Hanauer, et al. Live-attenuated bivalent measles virus derived vaccines targeting Middle East respiratory syndrome coronavirus induce robust and multifunctional T cell responses against both viruses in an appropriate mouse model. Virology, 2018, 521:99-107.
11. P.L. Fidel and M.C. Noverr. Could an unrelated live attenuated vaccine serve as a preventive measure to dampen septic inflammation associated with COVID-19 infection? mBio, DOI:10.1128/mBio.00907-20
12. S.K. Esher, P.L. Fidel, M.C. Noverr. Candida/staphylococcal polymicrobial intra-abdominal infection: pathogenesis and perspectives for a novel form of trained innate immunity. J. Fungi (Basel), 2019 Jun; 5(2): 37.
13. R. Franklin, A. Young, B. Neumann, et al. Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19. MedRxiv, doi: https://doi.org/10.1101/2020.04.10.20053207
14. M. Zheng, Y. Gao, G. Wang, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol., 2020 May, 17 (5), 533-535.
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