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The known unknowns of COVID-19 vaccines
Date: December 3, 2020 Author: Catharine Chambers
News that COVID-19 vaccines are up to 95 per cent effective has scientists cautiously optimistic. But questions remain.
“There’s a long list of things we don’t know,” says Maria Sundaram, a postdoctoral fellow at the Centre for Vaccine Preventable Diseases at the University of Toronto. Health Canada is currently reviewing early findings from Moderna, Pfizer/BioNTech and, more recently, the University of Oxford/AstraZeneca. All three show promise, but none have shared their full data, instead issuing a series of press releases.
The biggest unknowns are whether these results will hold up once full study findings are published and if a similar level of protection can be expected for other COVID-19 vaccines coming down the pipeline. The results could also change once these vaccines are rolled out on a population scale. We know that these vaccines work in clinical trials but we won’t know if their effectiveness will be the same in real-world scenarios.
“There’s no way that we can see that without a vaccine being licenced,” said Sundaram.
Although the trials included a diverse group of participants, including older adults and those from racial-ethnic minorities, it’s hard to know whether these findings will be generalizable to a broad range of people once the vaccines become available, experts say. For example, there is no information about how well this vaccine works in children. All three trials reported early results only in adults over the age of 18.
In addition, we don’t know if the vaccines prevent asymptomatic transmission.
“That’s something that is often an issue when designing vaccines for respiratory viruses that are administered intramuscularly,” according to Alyson Kelvin, a virologist with the Canadian Centre for Vaccinology at Dalhousie University who has recently been seconded to work on COVID-19 vaccines. “ When we give a vaccine in your arm, it’s often hard to get mucosal immunity in the upper respiratory tract,” like your nose, which is needed to stop transmission. A key for effective policy, she says, will be knowing whether someone who is vaccinated is still able to transmit the virus.
This illustration shows a cross section through a cell infected with a coronavirus such as SARS-CoV-2. It shows a time point when the virus is actively replicating, and new viruses are being created. The cell’s molecules are shown in blues and greens, and the viral molecules are shown in pinks and purples. Courtesy of David S. Goodsell, RCSB Protein Data Bank
Also unknown is how well the vaccines will work in people who have already had COVID-19 . A ll three studies excluded people with prior COVID-19 infection , although Pfizer/BioNTech and Oxford/AstraZeneca plan to look at this in a separate analysis.
As with all new vaccines, the length of protection has yet to be determined, since all three trials only began enrolling participants this summer. The companies have not disclosed how long participants were observed or whether any violated the study rules, which could change the initial efficacy estimates.
“Right now, we only have the interim data,” said Kelvin. We won’t know their long-term safety profile or whether they might cause rare side effects until after the vaccines are deployed to the public, although no safety issues have been identified to date.
“They seem to have a really positive safety profile. I haven’t seen anything that I am initially concerned with,” says Kelvin.
Protection could also be lower if people don’t adhere to the vaccine schedule. All three vaccines require two doses spaced at least three or four weeks apart.
“I think one really important question is: are people going to come back in for a second dose?” asks Sundaram. She says this might be an issue particularly if the first dose causes adverse reactions like a headache or fever.
Vaccine side effects may make people more hesitant to get vaccinated in the first place. In a StatsCan survey conducted before the recent vaccine announcements, about one in seven Canadians said they were unlikely to get a COVID-19 vaccine, citing a lack of confidence in safety and concerns about its side effects.
What about other COVID-19 vaccines in development?
All three vaccines reporting early results use newer technologies that deliver genetic material from the SARS-CoV-2 virus – either alone through what’s call messenger RNA (or mRNA, used by Pfizer/BioNTech and Moderna) or contained inside another virus or “vector” that can’t replicate on its own (Oxford/AstraZeneca). They then hijack the body’s own cells to make copies of the viral spike protein, the crown-like molecule protruding from the surface of the SARS-CoV-2 virus.
These types of vaccines have never been licenced before for use in humans.
Nine other COVID-19 vaccines are currently in late-stage trials, including four that rely on more conventional vaccine models using an inactivated (or killed) virus. These vaccines may elicit a more robust immune response that targets other viral components, not just the spike protein. They also may be better tolerated than some of the mRNA or viral vector vaccines based on earlier trial results.
Four are non-replicating viral vectors like the Oxford/AstraZeneca vaccine. These types of vaccines could have lower vaccine efficacy if people have pre-existing immunity to the vector. (Oxford/AstraZeneca tries to get around this by using a chimpanzee adenovirus, rather than a human one, as their vector.)
Others, like Novavax’s protein subunit vaccine, may be better able to generate a protective antibody response in the upper respiratory tract, which is important for blocking transmission, says Kelvin, whose lab is also developing a COVID-19 subunit vaccine.
Because they use different ways to trick the body’s immune system to produce antibodies, scientists can’t say whether these vaccines will be able to replicate the 90 to 95 per cent efficacy seen in the early trials.
“I don’t know what to expect. I’ll be honest with you,” states Sundaram. “I think it’s hard to use the results from these (three) studies to extrapolate to the other ones, especially for the other vaccine types.”
The number of doses, vaccination schedules and route of administration could also affect vaccine efficacy – along with patient factors such as age, underlying conditions and pre-existing immunity and viral factors such as genetic mutation. Experts say the latter is of less concern since SARS-CoV-2 doesn’t mutate as much as other RNA viruses, like influenza.
Looking ahead
While much remains unknown about these vaccines, these early results exceed the expectations of most scientists and bode well for other COVID-19 vaccines in development. Recently, Health Canada announced it would license a COVID-19 vaccine if it met a threshold of at least 50-per-cent efficacy.
The true impact of these new COVID-19 vaccines on curbing the pandemic will depend both on their efficacy but also their uptake on a population scale.
Given potential delays in vaccine manufacturing and rollout, a COVID-19 vaccine will likely not be enough to end the pandemic. But it will be another tool in our public health toolbox, alongside physical distancing, contact tracing and community supports, says Sundaram.
“As always, there’s more work to be done and further questions to be asked in Phase 4 studies,” says Sundaram. “But this is exactly the sort of direction that we would have hoped things would go. So, I’m very happy about that.”
Catharine Chambers is a PhD candidate and Vanier scholar at the Dalla Lana School of Public Health at the University of Toronto.
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Y. Cunnington December 3rd, 2020 at 12:31 pm
Some European experts have concerns about the rushing of the vaccines toward human use without adequate testing. On December 1, 2020, the ex-Pfizer head of respiratory research Dr. Michael Yeadon and the lung specialist and former head of the public health department Dr. Wolfgang Wodarg filed an application with the EMA, the European Medicine Agency responsible for EU-wide drug approval, for the immediate suspension of all SARS CoV 2 vaccine studies, in particular the BioNtech/Pfizer study on BNT162b (EudraCT number 2020-002641-42).
Dr. Wodarg and Dr. Yeadon demand that the studies – for the protection of the life and health of the volunteers – should not be continued until a study design is available that is suitable to address the significant safety concerns expressed by an increasing number of renowned scientists against the vaccine and the study design.
On the one hand, the petitioners demand that, due to the known lack of accuracy of the PCR test in a serious study, a so-called Sanger sequencing must be used. This is the only way to make reliable statements on the effectiveness of a vaccine against Covid-19. On the basis of the many different PCR tests of highly varying quality, neither the risk of disease nor a possible vaccine benefit can be determined with the necessary certainty, which is why testing the vaccine on humans is unethical per se.
Furthermore, they demand that it must be excluded, e.g. by means of animal experiments, that risks already known from previous studies, which partly originate from the nature of the corona viruses, can be realized. The concerns are directed in particular to the following points:
-The formation of so-called “non-neutralizing antibodies” can lead to an exaggerated immune reaction, especially when the test person is confronted with the real, “wild” virus after vaccination. This so-called antibody-dependent amplification, ADE, has long been known from experiments with corona vaccines in cats, for example. In the course of these studies all cats that initially tolerated the vaccination well died after catching the wild virus.
-The vaccinations are expected to produce antibodies against spike proteins of SARS-CoV-2. However, spike proteins also contain syncytin-homologous proteins, which are essential for the formation of the placenta in mammals such as humans. It must be absolutely ruled out that a vaccine against SARS-CoV-2 could trigger an immune reaction against syncytin-1, as otherwise infertility of indefinite duration could result in vaccinated women.
-The mRNA vaccines from BioNTech/Pfizer contain polyethylene glycol (PEG). 70% of people develop antibodies against this substance – this means that many people can develop allergic, potentially fatal reactions to the vaccination.
-The much too short duration of the study does not allow a realistic estimation of the late effects. As in the narcolepsy cases after the swine flu vaccination, millions of healthy people would be exposed to an unacceptable risk if an emergency approval were to be granted and the possibility of observing the late effects of the vaccination were to follow. Nevertheless, BioNTech/Pfizer apparently submitted an application for emergency approval on December 1, 2020.
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Mauritius Helmut Friedrich Josef Thisen December 5th, 2020 at 8:03 pm
Hej
What is in Phizer RNA Vaccin COMPLID ?
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The known unknowns of COVID-19 vaccines
Date: December 3, 2020 Author: Catharine Chambers
News that COVID-19 vaccines are up to 95 per cent effective has scientists cautiously optimistic. But questions remain.
“There’s a long list of things we don’t know,” says Maria Sundaram, a postdoctoral fellow at the Centre for Vaccine Preventable Diseases at the University of Toronto. Health Canada is currently reviewing early findings from Moderna, Pfizer/BioNTech and, more recently, the University of Oxford/AstraZeneca. All three show promise, but none have shared their full data, instead issuing a series of press releases.
The biggest unknowns are whether these results will hold up once full study findings are published and if a similar level of protection can be expected for other COVID-19 vaccines coming down the pipeline. The results could also change once these vaccines are rolled out on a population scale. We know that these vaccines work in clinical trials but we won’t know if their effectiveness will be the same in real-world scenarios.
“There’s no way that we can see that without a vaccine being licenced,” said Sundaram.
Although the trials included a diverse group of participants, including older adults and those from racial-ethnic minorities, it’s hard to know whether these findings will be generalizable to a broad range of people once the vaccines become available, experts say. For example, there is no information about how well this vaccine works in children. All three trials reported early results only in adults over the age of 18.
In addition, we don’t know if the vaccines prevent asymptomatic transmission.
“That’s something that is often an issue when designing vaccines for respiratory viruses that are administered intramuscularly,” according to Alyson Kelvin, a virologist with the Canadian Centre for Vaccinology at Dalhousie University who has recently been seconded to work on COVID-19 vaccines. “ When we give a vaccine in your arm, it’s often hard to get mucosal immunity in the upper respiratory tract,” like your nose, which is needed to stop transmission. A key for effective policy, she says, will be knowing whether someone who is vaccinated is still able to transmit the virus.
This illustration shows a cross section through a cell infected with a coronavirus such as SARS-CoV-2. It shows a time point when the virus is actively replicating, and new viruses are being created. The cell’s molecules are shown in blues and greens, and the viral molecules are shown in pinks and purples. Courtesy of David S. Goodsell, RCSB Protein Data Bank
Also unknown is how well the vaccines will work in people who have already had COVID-19 . A ll three studies excluded people with prior COVID-19 infection , although Pfizer/BioNTech and Oxford/AstraZeneca plan to look at this in a separate analysis.
As with all new vaccines, the length of protection has yet to be determined, since all three trials only began enrolling participants this summer. The companies have not disclosed how long participants were observed or whether any violated the study rules, which could change the initial efficacy estimates.
“Right now, we only have the interim data,” said Kelvin. We won’t know their long-term safety profile or whether they might cause rare side effects until after the vaccines are deployed to the public, although no safety issues have been identified to date.
“They seem to have a really positive safety profile. I haven’t seen anything that I am initially concerned with,” says Kelvin.
Protection could also be lower if people don’t adhere to the vaccine schedule. All three vaccines require two doses spaced at least three or four weeks apart.
“I think one really important question is: are people going to come back in for a second dose?” asks Sundaram. She says this might be an issue particularly if the first dose causes adverse reactions like a headache or fever.
Vaccine side effects may make people more hesitant to get vaccinated in the first place. In a StatsCan survey conducted before the recent vaccine announcements, about one in seven Canadians said they were unlikely to get a COVID-19 vaccine, citing a lack of confidence in safety and concerns about its side effects.
What about other COVID-19 vaccines in development?
All three vaccines reporting early results use newer technologies that deliver genetic material from the SARS-CoV-2 virus – either alone through what’s call messenger RNA (or mRNA, used by Pfizer/BioNTech and Moderna) or contained inside another virus or “vector” that can’t replicate on its own (Oxford/AstraZeneca). They then hijack the body’s own cells to make copies of the viral spike protein, the crown-like molecule protruding from the surface of the SARS-CoV-2 virus.
These types of vaccines have never been licenced before for use in humans.
Nine other COVID-19 vaccines are currently in late-stage trials, including four that rely on more conventional vaccine models using an inactivated (or killed) virus. These vaccines may elicit a more robust immune response that targets other viral components, not just the spike protein. They also may be better tolerated than some of the mRNA or viral vector vaccines based on earlier trial results.
Four are non-replicating viral vectors like the Oxford/AstraZeneca vaccine. These types of vaccines could have lower vaccine efficacy if people have pre-existing immunity to the vector. (Oxford/AstraZeneca tries to get around this by using a chimpanzee adenovirus, rather than a human one, as their vector.)
Others, like Novavax’s protein subunit vaccine, may be better able to generate a protective antibody response in the upper respiratory tract, which is important for blocking transmission, says Kelvin, whose lab is also developing a COVID-19 subunit vaccine.
Because they use different ways to trick the body’s immune system to produce antibodies, scientists can’t say whether these vaccines will be able to replicate the 90 to 95 per cent efficacy seen in the early trials.
“I don’t know what to expect. I’ll be honest with you,” states Sundaram. “I think it’s hard to use the results from these (three) studies to extrapolate to the other ones, especially for the other vaccine types.”
The number of doses, vaccination schedules and route of administration could also affect vaccine efficacy – along with patient factors such as age, underlying conditions and pre-existing immunity and viral factors such as genetic mutation. Experts say the latter is of less concern since SARS-CoV-2 doesn’t mutate as much as other RNA viruses, like influenza.
Looking ahead
While much remains unknown about these vaccines, these early results exceed the expectations of most scientists and bode well for other COVID-19 vaccines in development. Recently, Health Canada announced it would license a COVID-19 vaccine if it met a threshold of at least 50-per-cent efficacy.
The true impact of these new COVID-19 vaccines on curbing the pandemic will depend both on their efficacy but also their uptake on a population scale.
Given potential delays in vaccine manufacturing and rollout, a COVID-19 vaccine will likely not be enough to end the pandemic. But it will be another tool in our public health toolbox, alongside physical distancing, contact tracing and community supports, says Sundaram.
“As always, there’s more work to be done and further questions to be asked in Phase 4 studies,” says Sundaram. “But this is exactly the sort of direction that we would have hoped things would go. So, I’m very happy about that.”
Catharine Chambers is a PhD candidate and Vanier scholar at the Dalla Lana School of Public Health at the University of Toronto.
Leave a Comment
Comment
Your Comment
Yes, add me to your mailing list.
Enter the debate: reply to an existing comment
2 comments
Y. Cunnington December 3rd, 2020 at 12:31 pm
Some European experts have concerns about the rushing of the vaccines toward human use without adequate testing. On December 1, 2020, the ex-Pfizer head of respiratory research Dr. Michael Yeadon and the lung specialist and former head of the public health department Dr. Wolfgang Wodarg filed an application with the EMA, the European Medicine Agency responsible for EU-wide drug approval, for the immediate suspension of all SARS CoV 2 vaccine studies, in particular the BioNtech/Pfizer study on BNT162b (EudraCT number 2020-002641-42).
Dr. Wodarg and Dr. Yeadon demand that the studies – for the protection of the life and health of the volunteers – should not be continued until a study design is available that is suitable to address the significant safety concerns expressed by an increasing number of renowned scientists against the vaccine and the study design.
On the one hand, the petitioners demand that, due to the known lack of accuracy of the PCR test in a serious study, a so-called Sanger sequencing must be used. This is the only way to make reliable statements on the effectiveness of a vaccine against Covid-19. On the basis of the many different PCR tests of highly varying quality, neither the risk of disease nor a possible vaccine benefit can be determined with the necessary certainty, which is why testing the vaccine on humans is unethical per se.
Furthermore, they demand that it must be excluded, e.g. by means of animal experiments, that risks already known from previous studies, which partly originate from the nature of the corona viruses, can be realized. The concerns are directed in particular to the following points:
-The formation of so-called “non-neutralizing antibodies” can lead to an exaggerated immune reaction, especially when the test person is confronted with the real, “wild” virus after vaccination. This so-called antibody-dependent amplification, ADE, has long been known from experiments with corona vaccines in cats, for example. In the course of these studies all cats that initially tolerated the vaccination well died after catching the wild virus.
-The vaccinations are expected to produce antibodies against spike proteins of SARS-CoV-2. However, spike proteins also contain syncytin-homologous proteins, which are essential for the formation of the placenta in mammals such as humans. It must be absolutely ruled out that a vaccine against SARS-CoV-2 could trigger an immune reaction against syncytin-1, as otherwise infertility of indefinite duration could result in vaccinated women.
-The mRNA vaccines from BioNTech/Pfizer contain polyethylene glycol (PEG). 70% of people develop antibodies against this substance – this means that many people can develop allergic, potentially fatal reactions to the vaccination.
-The much too short duration of the study does not allow a realistic estimation of the late effects. As in the narcolepsy cases after the swine flu vaccination, millions of healthy people would be exposed to an unacceptable risk if an emergency approval were to be granted and the possibility of observing the late effects of the vaccination were to follow. Nevertheless, BioNTech/Pfizer apparently submitted an application for emergency approval on December 1, 2020.
Share
Reply to Y. Cunnington
Mauritius Helmut Friedrich Josef Thisen December 5th, 2020 at 8:03 pm
Hej
What is in Phizer RNA Vaccin COMPLID ?
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Reply to Mauritius Helmut Friedrich Josef Thisen
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