The world waits with bated breath as scientists across the globe race against time to find a vaccine against SARS-COV2. The good news is that its not a matter of whether, but when. Unlike some other viral infections, there are positive signs that a vaccine will certainly be possible. The virus itself stimulates an immune response which does result in neutralizing antibodies and viral clearance in vast majority of cases. The goal of a vaccine is to copy this, with much reduced risk. Vaccination is the only way we can reach herd immunity without loosing several thousands of excess lives in the process. However vaccines are made with different techniques and the companies making them have varying degrees of expertise in the field. I will try to explain the differences between these, assist in getting an understanding of the field and what factors to consider if a day eventually comes when we have an opportunity to choose which vaccine to take. It is clear that we need not one, but several candidate vaccines to be successful in order to satisfy the requirements of the world. Locally made candidate vaccines will have a particularly important role to play in equal distribution of vaccine and therefore I will pay particular note to vaccines being developed or produced in India.
Just like a tennis forehand can be described as classic, modern or next-gen, so can vaccine platforms.
1. Classic vaccine platforms:
These are the old time tested platforms being used for several existing vaccines. Broadly these can be divided into live attenuated, inactivated and fractionated / toxin vaccines. They have certain pros and cons and you would expect most large producers who have existing factory lines using these techniques to modify them for COVID19. We will discuss the first two types here as the third type is used primarily for production of bacterial vaccines such as Tetanus and Diphtheria toxoid.
a. Live Attenuated
Examples of current vaccines include BCG, MMRV, OPV , Rotavirus, Flumist Flu Nasal Spray, Zostavax , Oral Typhoid and Yellow Fever. Although some companies have proposed live attenuated virus vaccine for COVID19, none of them have yet entered human studies. The virus is attenuated ( weakened ) by growing it multiple times in a cell or egg yolk culture. This process can be time consuming , resource intensive and difficult to scale up due to the amount of material required, There is also risk of disease when injected to immune compromised patients as well as ineffective attenuation if proper lab processes are not followed. An example of this was the 1955 'Cutters Incident' in the USA soon after launch of polio vaccine. The vaccine was not attenuated properly by a certain lab which led to polio being transmitted to recipients of the live attenuated polio vaccine. Generally speaking a live vaccine for COVID19 would be considered a security risk not least due to the risk of transporting live SARS-COV2 virus in vials and syringes to administer it.
b. Inactivated
Examples of current vaccines include IPV and HIB. These vaccines are inactivated , usually by chemical ( e.g formaline ), heat or radiation. Covaxin, being produced by Bharat Biotech with ICMR and NIV belongs to this category. Chinese company Sinovac is also producing a similarly produced vaccine.
Both live attenuated and inactivated vaccines require production in high security facilities as they process hundreds of litres of live virus during production . The proteins within inactivated vaccines may be denatured during the process of inactivation and result in a sub optimal immune response. Therefore inactivated vaccines often require addition of adjuvants and several booster shots.
2. Modern Vaccine Platforms:
These are the platforms which within the last few decades have solved vaccination riddles which remained unsolved with older platforms. These use DNA recombinant technology in order to produce the desired antigen ( part of virus you wish to mount a defence against, such as spike protein of SARS-COV2 ) on a cell ( yeast, animal, insect , plant ) and then transport it into the human body to challenge the immune system and elicit an antibody response. The technology used here is similar to what is used to genetically modify foods and crops in order to make them resistant to pests and increase yield. Genetic labs utilise cleaving enzymes, plasmids and other tools to cut and paste genetic material and carry out ‘gene swapping’ like you would edit a video reel.
a. Protein Sub unit / Virus Like Particles
Existing vaccines include Shingrix , HBV Vaccine and HPV Vaccines
Shingrix is produced by instilling genetic material into hamster ovary cells to express varicella surface glycoprotein antigen. These cells injected into human body express the antigen and elicit an immune response.
HBV is manufactured by injecting genetic material encoding Hepatitis B surface antigen into yeast cells. The yeast cell injected into the body elicits an antibody response against the surface protein on Hepatitis B Virus.
HPV Vaccine is manufactured by inserting genetic material encoding HPV capsid protein into yeast cells. HPV Vaccine is particularly effective because the formed particles aggregate naturally into groups of VLP's ( virus like particles ) which elicit a particularly effective immune response.
DNA Recombinant protein sub unit vaccines for SARS-COV2 include Sanofi, University of Cambridge, University of Pittsburgh, three vaccines from Australia and two from Canada. Among the two Canadian vaccine candidates, Quebec based Medicago insert genetic material into insects which are then taken up by nicotine plants. The protein subunit is then 'cultivated' from tobacco leaves. This technique has been used to produce influenza vaccine in the past. Another Canadian vaccine candidate SK Biosciences is a collaboration between Saskatchewan and South Korea.
Novavax is developing a spike protein nanoparticle vaccine which will be produced by Serum Institute of India. The vaccine has been developed as a collaboration between USA and Australia and received 1.6 billion USD funding through operation warp speed.
b. DNA Recombinant Vector Vaccines
The only currently licensed vaccine in this category is Erbevo vaccine for Ebola virus. This was developed in Canada by University of Manitoba after a similar international vaccine race against Ebola. Here the RNA encoding the antigen is integrated into a benign live virus ( commonly Adenovirus ) and injected into the patient. This 'genetically modified' live virus expresses the required antigen to elicit an immune response.
SARS-COV2 candidates in this category include Oxford University / Astra Zeneca / Serum Institute of India, CanSino ( Hong Kong based collaboration between Canada and China ) and Harvard University / Johnson & Johnson in USA. Oxford and Cansino are the most advanced vaccines at present having moved into phase 3 trials. At this time Cansino is the only vaccine which had it's phase 2 trial results published in a journal ( Lancet ).
VBI Vaccines is a company with headquarters in USA and research in Ottawa, Canada which is developing a 'Pan Coronavirus' Vaccine. This would be a virus like protein which would immunize against not just SARS-COV2, but also its cousins MERS and SARS-1 !
Perhaps even more impressive is Coroflu, a collaboration between University of Wisconsin and Bharat Biotech. The vector in this case is a weakened influenza virus which is administered as a nose drop. This influenza virus has been genetically restricted to a single round of multiplication and SARS-COV2 RNA is coded onto it. Amazingly this intranasal vaccine will provide immunity against both COVID19 as well as Influenza ! Hint of caution however as some intranasal flu vaccines have elicited erratic immune responses in the past, such as Flumist.
Vaccine developers for SARS-COV2 are targeting its spike protein , which is responsible for its entry into target cells. I feel that this technology is most likely to yield a safe and effective vaccine. Such vaccines can be expensive to develop however since they contain both a DNA recombination and hybrid cell culturing phase.
Next Generation Vaccine Platforms:
These are vaccines which are designed the bypass the DNA recombination phase step of protein sub-unit vaccines. Rather than instilling DNA or RNA into a yeast cell or live virus, inject it directly into the patient. Coat the genetic material in a lipid membrane so that it gets taken up by host cells. The vaccine recipients own cells will then express the antigens and develop an antibody response. While this technique has led to development of vaccines for animals, none have been licensed for human use yet. The closest so far is USA based Inovio which in collaboration with South Korea managed to clear phase 1 trials for MERS.
SARS-COV2 vaccine candidates in this category include:
a. DNA vaccine
Innovio ( USA and South Korea )
Zydus Cadila ( India )
b. mRNA
Moderna ( USA )
Imperial College, London
Next generation vaccines represent the largest number of vaccine developers at present against Covid19 . Why so much effort for an untried platform you may wonder. The main two reasons are speed and efficiency. As soon as the RNA sequence of SARS-COV2 was made public on the 11th of January 2020, labs across the world working on this platform got a head start to develop a vaccine. This kind of vaccine can be produced quicker, at relatively low cost and scaled up significantly for large scale production. These vaccines can also be made thermostable and transported with minimal cold chain requirements . So while the technology is untested for humans, rewards will be significant if it pulls through. It’s a high risk and high reward strategy.
In summary, vaccination for SARS-COV2 will certainly be the 'end game'. Science and Technology will save us from this Pandemic and we should be thankful to not just the frontline workers , but also the scientists, biotechnologists and businesses working day and night to produce a vaccine against COVID19. At Bharat Bio-tech's high security vaccine production plant for instance, staff are not allowed to visit their families and have been living at the plant for several months. This is because they handle live SARS-COV2 virus during production of this vaccine and leaving the plant would risk leakage into the community. As a global community we need not one, but several successful vaccines in order to service the needs of our planet. Below are my Top Picks among Virus candidates available in India with reasons why.
1. Novavax / Serum Institute of India ( USA / Australia)
This is a case of choosing a modern tennis forehand over a classic or next generation one. My Top 3 vaccine picks are based upon DNA Recombinant technology which is modern as well as proven. This has delivered us vaccines such as HBV, HPV and Shingrix. The largest injection of funding ( USD 1.6 billion ) from Operation Warp Speed was secured by Novavax and is testament to this technologies promise.
2. Oxford University ( UK ) / Serum Institute of India
Oxford University candidates use of a viral vector poses some additional challenges but is also a proven technology, used previously for Ebola. Since this vaccine is in phase 3 trials, it may well become the first one to be licenced ( along with Can-Sino which is also based on a similar platform).
3. Coroflu: University of Wisconcin ( USA ) / Serum Institute of India : While this is another vaccine which could be described as a DNA recombinant virus vector vaccine, administration intranasally potentially makes this vaccine less reliable and study results will have to be studied closely.
4. Covaxin: Bharat Biotech / ICMR / NIV : Inactivated vaccine is relatively an 'older technology' and one which had not provided solutions for more recent challenges such as HBV, HPV, Ebola and MERS. It would be fantastic if SARS-COV2 is neutralized with this technology, but the scale of challenge is such, that this may not be possible. Results of phase 1 to 3 trials should be monitored closely for efficacy.
5. Zydus Cadila : This DNA vaccine platform is unproven up to now. The best that USA based Innovio was able to accomplish was phase one clearance for MERS. We should applaud and support these efforts but this is not a platform I would hedge bets on. If a DNA vaccine platform succeeds, however it could actually prove to be the most cost effective, easily mass produced and thermostable vaccine.
I hope that all these vaccine candidates succeed off course. The world needs several winners, not just one. I anticipate that a COVID19 vaccine will be licensed in the New Year. Due to regulatory frameworks this may be slightly earlier in the Eastern Hemisphere and later in the West.
Just like a tennis forehand can be described as classic, modern or next-gen, so can vaccine platforms.
1. Classic vaccine platforms:
These are the old time tested platforms being used for several existing vaccines. Broadly these can be divided into live attenuated, inactivated and fractionated / toxin vaccines. They have certain pros and cons and you would expect most large producers who have existing factory lines using these techniques to modify them for COVID19. We will discuss the first two types here as the third type is used primarily for production of bacterial vaccines such as Tetanus and Diphtheria toxoid.
a. Live Attenuated
Examples of current vaccines include BCG, MMRV, OPV , Rotavirus, Flumist Flu Nasal Spray, Zostavax , Oral Typhoid and Yellow Fever. Although some companies have proposed live attenuated virus vaccine for COVID19, none of them have yet entered human studies. The virus is attenuated ( weakened ) by growing it multiple times in a cell or egg yolk culture. This process can be time consuming , resource intensive and difficult to scale up due to the amount of material required, There is also risk of disease when injected to immune compromised patients as well as ineffective attenuation if proper lab processes are not followed. An example of this was the 1955 'Cutters Incident' in the USA soon after launch of polio vaccine. The vaccine was not attenuated properly by a certain lab which led to polio being transmitted to recipients of the live attenuated polio vaccine. Generally speaking a live vaccine for COVID19 would be considered a security risk not least due to the risk of transporting live SARS-COV2 virus in vials and syringes to administer it.
b. Inactivated
Examples of current vaccines include IPV and HIB. These vaccines are inactivated , usually by chemical ( e.g formaline ), heat or radiation. Covaxin, being produced by Bharat Biotech with ICMR and NIV belongs to this category. Chinese company Sinovac is also producing a similarly produced vaccine.
Both live attenuated and inactivated vaccines require production in high security facilities as they process hundreds of litres of live virus during production . The proteins within inactivated vaccines may be denatured during the process of inactivation and result in a sub optimal immune response. Therefore inactivated vaccines often require addition of adjuvants and several booster shots.
2. Modern Vaccine Platforms:
These are the platforms which within the last few decades have solved vaccination riddles which remained unsolved with older platforms. These use DNA recombinant technology in order to produce the desired antigen ( part of virus you wish to mount a defence against, such as spike protein of SARS-COV2 ) on a cell ( yeast, animal, insect , plant ) and then transport it into the human body to challenge the immune system and elicit an antibody response. The technology used here is similar to what is used to genetically modify foods and crops in order to make them resistant to pests and increase yield. Genetic labs utilise cleaving enzymes, plasmids and other tools to cut and paste genetic material and carry out ‘gene swapping’ like you would edit a video reel.
a. Protein Sub unit / Virus Like Particles
Existing vaccines include Shingrix , HBV Vaccine and HPV Vaccines
Shingrix is produced by instilling genetic material into hamster ovary cells to express varicella surface glycoprotein antigen. These cells injected into human body express the antigen and elicit an immune response.
HBV is manufactured by injecting genetic material encoding Hepatitis B surface antigen into yeast cells. The yeast cell injected into the body elicits an antibody response against the surface protein on Hepatitis B Virus.
HPV Vaccine is manufactured by inserting genetic material encoding HPV capsid protein into yeast cells. HPV Vaccine is particularly effective because the formed particles aggregate naturally into groups of VLP's ( virus like particles ) which elicit a particularly effective immune response.
DNA Recombinant protein sub unit vaccines for SARS-COV2 include Sanofi, University of Cambridge, University of Pittsburgh, three vaccines from Australia and two from Canada. Among the two Canadian vaccine candidates, Quebec based Medicago insert genetic material into insects which are then taken up by nicotine plants. The protein subunit is then 'cultivated' from tobacco leaves. This technique has been used to produce influenza vaccine in the past. Another Canadian vaccine candidate SK Biosciences is a collaboration between Saskatchewan and South Korea.
Novavax is developing a spike protein nanoparticle vaccine which will be produced by Serum Institute of India. The vaccine has been developed as a collaboration between USA and Australia and received 1.6 billion USD funding through operation warp speed.
b. DNA Recombinant Vector Vaccines
The only currently licensed vaccine in this category is Erbevo vaccine for Ebola virus. This was developed in Canada by University of Manitoba after a similar international vaccine race against Ebola. Here the RNA encoding the antigen is integrated into a benign live virus ( commonly Adenovirus ) and injected into the patient. This 'genetically modified' live virus expresses the required antigen to elicit an immune response.
SARS-COV2 candidates in this category include Oxford University / Astra Zeneca / Serum Institute of India, CanSino ( Hong Kong based collaboration between Canada and China ) and Harvard University / Johnson & Johnson in USA. Oxford and Cansino are the most advanced vaccines at present having moved into phase 3 trials. At this time Cansino is the only vaccine which had it's phase 2 trial results published in a journal ( Lancet ).
VBI Vaccines is a company with headquarters in USA and research in Ottawa, Canada which is developing a 'Pan Coronavirus' Vaccine. This would be a virus like protein which would immunize against not just SARS-COV2, but also its cousins MERS and SARS-1 !
Perhaps even more impressive is Coroflu, a collaboration between University of Wisconsin and Bharat Biotech. The vector in this case is a weakened influenza virus which is administered as a nose drop. This influenza virus has been genetically restricted to a single round of multiplication and SARS-COV2 RNA is coded onto it. Amazingly this intranasal vaccine will provide immunity against both COVID19 as well as Influenza ! Hint of caution however as some intranasal flu vaccines have elicited erratic immune responses in the past, such as Flumist.
Vaccine developers for SARS-COV2 are targeting its spike protein , which is responsible for its entry into target cells. I feel that this technology is most likely to yield a safe and effective vaccine. Such vaccines can be expensive to develop however since they contain both a DNA recombination and hybrid cell culturing phase.
Next Generation Vaccine Platforms:
These are vaccines which are designed the bypass the DNA recombination phase step of protein sub-unit vaccines. Rather than instilling DNA or RNA into a yeast cell or live virus, inject it directly into the patient. Coat the genetic material in a lipid membrane so that it gets taken up by host cells. The vaccine recipients own cells will then express the antigens and develop an antibody response. While this technique has led to development of vaccines for animals, none have been licensed for human use yet. The closest so far is USA based Inovio which in collaboration with South Korea managed to clear phase 1 trials for MERS.
SARS-COV2 vaccine candidates in this category include:
a. DNA vaccine
Innovio ( USA and South Korea )
Zydus Cadila ( India )
b. mRNA
Moderna ( USA )
Imperial College, London
Next generation vaccines represent the largest number of vaccine developers at present against Covid19 . Why so much effort for an untried platform you may wonder. The main two reasons are speed and efficiency. As soon as the RNA sequence of SARS-COV2 was made public on the 11th of January 2020, labs across the world working on this platform got a head start to develop a vaccine. This kind of vaccine can be produced quicker, at relatively low cost and scaled up significantly for large scale production. These vaccines can also be made thermostable and transported with minimal cold chain requirements . So while the technology is untested for humans, rewards will be significant if it pulls through. It’s a high risk and high reward strategy.
In summary, vaccination for SARS-COV2 will certainly be the 'end game'. Science and Technology will save us from this Pandemic and we should be thankful to not just the frontline workers , but also the scientists, biotechnologists and businesses working day and night to produce a vaccine against COVID19. At Bharat Bio-tech's high security vaccine production plant for instance, staff are not allowed to visit their families and have been living at the plant for several months. This is because they handle live SARS-COV2 virus during production of this vaccine and leaving the plant would risk leakage into the community. As a global community we need not one, but several successful vaccines in order to service the needs of our planet. Below are my Top Picks among Virus candidates available in India with reasons why.
1. Novavax / Serum Institute of India ( USA / Australia)
This is a case of choosing a modern tennis forehand over a classic or next generation one. My Top 3 vaccine picks are based upon DNA Recombinant technology which is modern as well as proven. This has delivered us vaccines such as HBV, HPV and Shingrix. The largest injection of funding ( USD 1.6 billion ) from Operation Warp Speed was secured by Novavax and is testament to this technologies promise.
2. Oxford University ( UK ) / Serum Institute of India
Oxford University candidates use of a viral vector poses some additional challenges but is also a proven technology, used previously for Ebola. Since this vaccine is in phase 3 trials, it may well become the first one to be licenced ( along with Can-Sino which is also based on a similar platform).
3. Coroflu: University of Wisconcin ( USA ) / Serum Institute of India : While this is another vaccine which could be described as a DNA recombinant virus vector vaccine, administration intranasally potentially makes this vaccine less reliable and study results will have to be studied closely.
4. Covaxin: Bharat Biotech / ICMR / NIV : Inactivated vaccine is relatively an 'older technology' and one which had not provided solutions for more recent challenges such as HBV, HPV, Ebola and MERS. It would be fantastic if SARS-COV2 is neutralized with this technology, but the scale of challenge is such, that this may not be possible. Results of phase 1 to 3 trials should be monitored closely for efficacy.
5. Zydus Cadila : This DNA vaccine platform is unproven up to now. The best that USA based Innovio was able to accomplish was phase one clearance for MERS. We should applaud and support these efforts but this is not a platform I would hedge bets on. If a DNA vaccine platform succeeds, however it could actually prove to be the most cost effective, easily mass produced and thermostable vaccine.
I hope that all these vaccine candidates succeed off course. The world needs several winners, not just one. I anticipate that a COVID19 vaccine will be licensed in the New Year. Due to regulatory frameworks this may be slightly earlier in the Eastern Hemisphere and later in the West.
INFORMATION & DISCLAIMER:
I obtained my primary medical education from India and post graduate MD in Family Medicine from the United Kingdom. After working in the NHS for 15 years, I moved to Canada five years ago. As a Family Physician, my specialty is engaging patients, interpreting medical information for them, guiding them through their health journey, promoting wise health choices and encouraging early detection and management of disease. The information on this blog is accurate as per time of publishing and patients should check the main blog for updates. Scientific information and evidence changes dynamically and my opinions would change accordingly. The recommendations on this blog are not prescriptions and any patients considering these should consult with a physician to check if these are applicable to their unique case. Patient confidentiality must be upheld at all times and any patients wishing to discuss specific medical scenarios on social media are requested to do so anonymously in 'third party' sense.
Subscribe to Youtube Channel
https://www.youtube.com/channel/UCnCy6G8OIft6WgHz7UK35kg
Follow Facebook Page
https://www.facebook.com/Health-Talk-with-Dr-S-S-Rawat-106181777973272/
Thanks for sharing such a important issue Dr.Rawat .
ReplyDelete