Afra Shamnath
Vaccines are biological agents which can elicit an immune response in the host and protect against infection or diseases caused by pathogens. Vaccination therefore is one of the most effective and widely employed tools to prevent infections and or death due to specific pathogens. A number of vaccines are now widely employed as a public health strategy to prevent disease, disability and deaths. It is heartening to note that effective vaccination could practically eradicate some of the deadly infections known to mankind. Smallpox is the only disease that has been eradicated globally [1]. Other examples of regional eradication include diseases like Polio [2]. Additionally many diseases like measles and mumps which manifest mostly during childhood have been managed effectively through mass vaccinations as a public health measure [3].
Vaccines are designed to minimise potential infection and disease caused by specific pathogenic organisms. A breakthrough infection is an infection occurring in individuals vaccinated against a specific pathogen or disease. It may occur due to various reasons. The inapt handling, storage or administration of vaccines could be one. Several instances of antibody blocking or escape mutants have also been reported which hamper the efficacy and effectiveness of the vaccine [4]. Immunosenescence or the process of the immune system ageing could be another factor that contributes to the same [5]. Breakthrough infections are therefore important to assess and evaluate since they are of epidemiological significance in assessing vaccine strategies, as well as coverage and efficacy of vaccines [6].
While all viruses evolve by accumulating genetic variants, it is noteworthy that a small subset of the variants could impact the ability of the virus to escape specific arms of the immune system. Briefly the adaptive immune system to viral pathogens encompasses two arms, modulated by the B cells which form antibodies against a pathogen and the T-cells which modulate cytotoxic response against cells harbouring the virus. These two arms work in tandem to clear infection and / or prevent the disease caused by the pathogen. The B-cell response is modulated by specific receptors which recognise portions of the proteins in the pathogen and elicit antibodies which can bind to the proteins, while the T-cell response is mediated by an elaborate system of digesting viral proteins, and presenting them to T-cells using the Major Histocompatibility Complex molecules.
Genetic variants in the virus which could interfere with any of the above mechanisms of molecular recognition or the effective binding and /or neutralisation of human antibodies to the cognate pathogen protein could therefore be broadly classified as immune escape mutations.
Several antibody escape variants have been identified to this date. Most common immune escape variants have been identified in at least four diseases across the world Hepatitis B virus, Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenzae (non-type b) meningitis[7]. Immune escapes could mean more people who have already been affected may still remain prone to reinfection and that vaccines will need an update.
The last one year has witnessed one of the largest pandemics in recent human memory. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) claimed millions of lives worldwide. Even when the world took a standstill, the race to develop a vaccine never ceased. Less than two months after the first outbreak, on January 11, 2020 Chinese scientists released the first genetic sequence of the virus that became the beacon of hope for vaccine researchers and scientists to model vaccines. In December 2020, drug giants developed vaccines that were approved for emergency use. Even with millions of inoculations, there still have been occurrences of reinfection.
As of March 2, 2021, there are 6 vaccines in early or limited use. Another 6 vaccines are approved for full use (outside the United States) and 20 vaccines are in phase 3 clinical trials. There are generally four types of vaccines namely, Whole virion vaccines , mRNA vaccines, non replicating viral vector vaccines and protein subunit vaccines.
A Whole virion vaccine uses inactivated or weakened form of a pathogen that causes the immune system to trigger a response. Sinopharm, Sinovac are two whole virus vaccines currently being used. Two doses are required intramuscularly and booster doses may be needed. A whole virus vaccine is comparatively suitable for immunocompromised individuals and is relatively easier to manufacture[7].
A RNA or mRNA vaccine consists of mRNA molecules that in this case, generally code for the spike protein of the SARS-CoV-2 virus. Once injected, the mRNA instructs the cells to produce spike protein. These are then detected by immune cells which trigger a response by the body’s lymphocytes. The killer T-cells destroy the infected cells, while the B-cells and helper T-cells support antibody production. Whoever is exposed to the COVID-19 coronavirus in the future would have an immune system that recognises it, and in turn fight the infection. Pfizer-BioNTech, Moderna are two mRNA vaccines which require two doses intramuscularly [8].
Non replicating viral vector vaccines consist of non-replicating viruses with recombinant viral immunogenic proteins which can instruct the body to produce a large amount of antigens, which in turn trigger an immune response. Oxford-AstraZeneca, Sputnik V (Gamaleya Research Institute) are examples of Non replicating viral vectors. It requires two doses intramuscularly. Vaccines for Ebola were based on these vaccines [9].
Protein Subunit Vaccine contains parts or whole of viral proteins rather than the whole pathogen to trigger an immune response. Novavax is an example of a Protein subunit vaccine. Similar vaccines are used for Hepatitis B, meningococcal disease, pneumococcal disease and shingles [10].
How genomics can help
Vaccines are biological agents which can elicit an immune response in the host and protect against infection or diseases caused by pathogens. Vaccination therefore is one of the most effective and widely employed tools to prevent infections and or death due to specific pathogens. A number of vaccines are now widely employed as a public health strategy to prevent disease, disability and deaths. It is heartening to note that effective vaccination could practically eradicate some of the deadly infections known to mankind. Smallpox is the only disease that has been eradicated globally [1]. Other examples of regional eradication include diseases like Polio [2]. Additionally many diseases like measles and mumps which manifest mostly during childhood have been managed effectively through mass vaccinations as a public health measure [3].
Vaccines are designed to minimise potential infection and disease caused by specific pathogenic organisms. A breakthrough infection is an infection occurring in individuals vaccinated against a specific pathogen or disease. It may occur due to various reasons. The inapt handling, storage or administration of vaccines could be one. Several instances of antibody blocking or escape mutants have also been reported which hamper the efficacy and effectiveness of the vaccine [4]. Immunosenescence or the process of the immune system ageing could be another factor that contributes to the same [5]. Breakthrough infections are therefore important to assess and evaluate since they are of epidemiological significance in assessing vaccine strategies, as well as coverage and efficacy of vaccines [6].
While all viruses evolve by accumulating genetic variants, it is noteworthy that a small subset of the variants could impact the ability of the virus to escape specific arms of the immune system. Briefly the adaptive immune system to viral pathogens encompasses two arms, modulated by the B cells which form antibodies against a pathogen and the T-cells which modulate cytotoxic response against cells harbouring the virus. These two arms work in tandem to clear infection and / or prevent the disease caused by the pathogen. The B-cell response is modulated by specific receptors which recognise portions of the proteins in the pathogen and elicit antibodies which can bind to the proteins, while the T-cell response is mediated by an elaborate system of digesting viral proteins, and presenting them to T-cells using the Major Histocompatibility Complex molecules.
Genetic variants in the virus which could interfere with any of the above mechanisms of molecular recognition or the effective binding and /or neutralisation of human antibodies to the cognate pathogen protein could therefore be broadly classified as immune escape mutations.
Several antibody escape variants have been identified to this date. Most common immune escape variants have been identified in at least four diseases across the world Hepatitis B virus, Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenzae (non-type b) meningitis[7]. Immune escapes could mean more people who have already been affected may still remain prone to reinfection and that vaccines will need an update.
The last one year has witnessed one of the largest pandemics in recent human memory. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) claimed millions of lives worldwide. Even when the world took a standstill, the race to develop a vaccine never ceased. Less than two months after the first outbreak, on January 11, 2020 Chinese scientists released the first genetic sequence of the virus that became the beacon of hope for vaccine researchers and scientists to model vaccines. In December 2020, drug giants developed vaccines that were approved for emergency use. Even with millions of inoculations, there still have been occurrences of reinfection.
As of March 2, 2021, there are 6 vaccines in early or limited use. Another 6 vaccines are approved for full use (outside the United States) and 20 vaccines are in phase 3 clinical trials. There are generally four types of vaccines namely, Whole virion vaccines , mRNA vaccines, non replicating viral vector vaccines and protein subunit vaccines.
A Whole virion vaccine uses inactivated or weakened form of a pathogen that causes the immune system to trigger a response. Sinopharm, Sinovac are two whole virus vaccines currently being used. Two doses are required intramuscularly and booster doses may be needed. A whole virus vaccine is comparatively suitable for immunocompromised individuals and is relatively easier to manufacture[7].
A RNA or mRNA vaccine consists of mRNA molecules that in this case, generally code for the spike protein of the SARS-CoV-2 virus. Once injected, the mRNA instructs the cells to produce spike protein. These are then detected by immune cells which trigger a response by the body’s lymphocytes. The killer T-cells destroy the infected cells, while the B-cells and helper T-cells support antibody production. Whoever is exposed to the COVID-19 coronavirus in the future would have an immune system that recognises it, and in turn fight the infection. Pfizer-BioNTech, Moderna are two mRNA vaccines which require two doses intramuscularly [8].
Non replicating viral vector vaccines consist of non-replicating viruses with recombinant viral immunogenic proteins which can instruct the body to produce a large amount of antigens, which in turn trigger an immune response. Oxford-AstraZeneca, Sputnik V (Gamaleya Research Institute) are examples of Non replicating viral vectors. It requires two doses intramuscularly. Vaccines for Ebola were based on these vaccines [9].
Protein Subunit Vaccine contains parts or whole of viral proteins rather than the whole pathogen to trigger an immune response. Novavax is an example of a Protein subunit vaccine. Similar vaccines are used for Hepatitis B, meningococcal disease, pneumococcal disease and shingles [10].
How genomics can help
Genome sequencing of SARS-CoV-2 has enabled scientists around the globe to understand the evolution and genetic epidemiology of the virus as it spread across the world [11]. Viral genomes inherently evolve with time. Therefore genomic surveillance is crucial in keeping track of the escape mutants that may arise. The efforts to sequence viruses in a temporal fashion has undoubtedly in recent years also enabled dth detection of emerging lineages of the SARS-COV-2 virus including some lineages which are associated with immune escape as well as increased infectivity [12]. This has enabled the implementation as well as validation of public health policies.
Understanding the genomes of emerging breakthrough infections would indeed be invaluable to understand the genetic underpinnings of how the virus evades the immune response elicited by vaccines. A global compendium of such sequences could enable tracking of emerging variants and also advise policy on containing the spread of the virus. Not to mention that such insights would be invaluable in developing better vaccines for SARS_CoV-2.
A research initiative at CSIR Institute of Genomics and Integrative Biology has been investigating the genetic underpinnings of COVID-19 reinfections in India [13]. This has resulted in uncovering the first cases of asymptomatic reinfections as well as being able to genetically characterized re-activations as well as reinfections associated with immune escape variants in SARS-CoV-2 [14-16]. This programme additionally now tracks cases of breakthrough infections as they emerge in India. The website portal (https://reinfections.genomes.in/) provides more information on the programme as well as instructions to refer cases of breakthrough infections.
References
1. Smallpox. Lancet 367, 425–435 (2006).
2. Website. doi: https://doi.org/10.1136/bmj.286.6358.31.
3. Restif, O. & Grenfell, B. T. Vaccination and the dynamics of immune evasion. J. R. Soc. Interface 4, 143–153 (2007).
4. Website. doi: https://doi.org/10.1101/2021.02.18.431922.
5. Lord, J. M. The effect of ageing of the immune system on vaccination responses. Hum. Vaccin. Immunother. 9, 1364–1367 (2013).
6. Distinguishing vaccine efficacy and effectiveness. Vaccine 30, 6700–6705 (2012).
7. Website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html. Accessed Feb. 2, 2021.
8. Website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html.
9. Website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/viralvector.html. Accessed Feb. 2, 2021.
10. Website. https://www.who.int/news-room/feature-stories/detail/the-race-for-a-covid-19-vaccine-explained.
11. WHO | SARS-CoV-2 Variants. (2021).
12. Website. doi: http://dx.doi.org/10.2471/BLT.20.253591.
13. Website.
14. Gupta, V. et al. Asymptomatic Reinfection in 2 Healthcare Workers From India With Genetically Distinct Severe Acute Respiratory Syndrome Coronavirus 2. Clin. Infect. Dis. (2020) doi:10.1093/cid/ciaa1451.
15. Asymptomatic reactivation of SARS-CoV-2 in a child with neuroblastoma characterised by whole genome sequencing. IDCases 23, e01018 (2021).
16. Rani, P. R. et al. Symptomatic reinfection of SARS-CoV-2 with spike protein variant N440K associated with immune escape. doi:10.31219/osf.io/7gk69.
About the author
The author is a researcher at the CSIR-IGIB . All opinions expressed are personal and do not reflect the opinion of their employers or organisations associated. The Author can be reached at @AfraShamnath on Twitter
Understanding the genomes of emerging breakthrough infections would indeed be invaluable to understand the genetic underpinnings of how the virus evades the immune response elicited by vaccines. A global compendium of such sequences could enable tracking of emerging variants and also advise policy on containing the spread of the virus. Not to mention that such insights would be invaluable in developing better vaccines for SARS_CoV-2.
A research initiative at CSIR Institute of Genomics and Integrative Biology has been investigating the genetic underpinnings of COVID-19 reinfections in India [13]. This has resulted in uncovering the first cases of asymptomatic reinfections as well as being able to genetically characterized re-activations as well as reinfections associated with immune escape variants in SARS-CoV-2 [14-16]. This programme additionally now tracks cases of breakthrough infections as they emerge in India. The website portal (https://reinfections.genomes.in/) provides more information on the programme as well as instructions to refer cases of breakthrough infections.
References
1. Smallpox. Lancet 367, 425–435 (2006).
2. Website. doi: https://doi.org/10.1136/bmj.286.6358.31.
3. Restif, O. & Grenfell, B. T. Vaccination and the dynamics of immune evasion. J. R. Soc. Interface 4, 143–153 (2007).
4. Website. doi: https://doi.org/10.1101/2021.02.18.431922.
5. Lord, J. M. The effect of ageing of the immune system on vaccination responses. Hum. Vaccin. Immunother. 9, 1364–1367 (2013).
6. Distinguishing vaccine efficacy and effectiveness. Vaccine 30, 6700–6705 (2012).
7. Website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html. Accessed Feb. 2, 2021.
8. Website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html.
9. Website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/viralvector.html. Accessed Feb. 2, 2021.
10. Website. https://www.who.int/news-room/feature-stories/detail/the-race-for-a-covid-19-vaccine-explained.
11. WHO | SARS-CoV-2 Variants. (2021).
12. Website. doi: http://dx.doi.org/10.2471/BLT.20.253591.
13. Website.
14. Gupta, V. et al. Asymptomatic Reinfection in 2 Healthcare Workers From India With Genetically Distinct Severe Acute Respiratory Syndrome Coronavirus 2. Clin. Infect. Dis. (2020) doi:10.1093/cid/ciaa1451.
15. Asymptomatic reactivation of SARS-CoV-2 in a child with neuroblastoma characterised by whole genome sequencing. IDCases 23, e01018 (2021).
16. Rani, P. R. et al. Symptomatic reinfection of SARS-CoV-2 with spike protein variant N440K associated with immune escape. doi:10.31219/osf.io/7gk69.
About the author
The author is a researcher at the CSIR-IGIB . All opinions expressed are personal and do not reflect the opinion of their employers or organisations associated. The Author can be reached at @AfraShamnath on Twitter
nicely explained!!
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