[BostonCard]

What is considered acceptable, risk wise?  I’m talking in general for a vaccine?  And does that change in a pandemic?  In other words, is the acceptable risk increased a bit?

In general, because a vaccine is going into people that start out healthy, the tolerance for risk is going to be low, and the safety bar is going to be high.  That will probably change in the context of a pandemic, but there is still a fundamental problem which is that the people who harmed by a vaccine are easily identifiable (and some may even ascribe coincidental but unrelated ailments to the vaccine, as was the case with the MMR vaccine and autism), while the people who benefit are unidentifiable.  If you get vaccinated and don't get symptomatic coronavirus infection, you have no way of knowing whether that was because you got vaccinated or whether you would have been one of the many people who don't get symptomatic disease.

I do think that in the context of a pandemic, the safety bar ought to be relaxed a bit (within reason), as the number of people whose lives can be saved by a vaccine will number in the hundreds of thousands in the US alone, and the number harmed will be a lot lower even with a somewhat relaxed safety bar.  On the flip side, that has to be balanced against a small but vocal minority of people who are very distrustful of vaccines and could amplify their anti-vaccination message.  A vaccine that is ultimately deemed to be unsafe in the court of public opinion would be a disaster.  I wish it weren't so.

You can get an idea of what the safety bar has been historically from vaccines that have been withdrawn or restricted from the market for safety reasons:

For rotavirus:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462159/

The first rotavirus vaccine (RotaShield (Rotavirus, Live, Oral, Tetravalent – Wyeth)was licensed and recommended for routine use in the US by the Advisory Committee on Immunization Practices (ACIP) in 1998.5 This vaccine, was evaluated in 18,000 infants. A summary of the pre-licensing trials reported five cases of intussusception among 10,054 infants receiving vaccine and one case in 4,633 placebo patients (0.05% vs. 0.02%, P > .45). The FDA approved the vaccine on August 31, 1998, and the ACIP recommended routine use the following October for infants at age 2, 4, and six months. On July 16, 1999, the Vaccine Adverse Event Reporting Systems (VAERS) reported 15 cases of intussusception among recipients.6 The CDC placed a temporary suspension on routine administration until a case control investigation could evaluate these cases.7 This investigation demonstrated a strong relationship between RotaShield and intussusception, prompting the ACIP to withdraw its recommendation for routine use in October, 1999.8 The manufacturer voluntarily withdrew this product from the market shortly thereafter.

For dengue:
https://www.virology.ws/2017/12/07/a-pro...s-vaccine/

The numbers are small but significant. For example, during year 5 after the third dose of vaccine, 295 of 20,439 children (1.44%) were hospitalized with dengue virus infection. Severe dengue was also observed during years 2-4 after the third dose. Considering that millions of children will eventually receive this vaccine, serious disease occurring at a rate of 1.44% is not acceptable.

For H1N1 influenza:
https://jamanetwork.com/journals/jama/fu...le/1216476

Results Over a 6-month period, 83 confirmed GBS cases were identified, including 71 Brighton level 1 through 3 cases. Twenty-five confirmed cases had been vaccinated against 2009 influenza A(H1N1) 8 or fewer weeks before disease onset, with most (19/25) vaccinated 4 or fewer weeks before onset. In the Poisson model, the age- and sex-adjusted relative risk was 1.80 (95% CI, 1.12-2.87) for all confirmed cases during the 8-week postvaccination period and was 2.75 (95% CI, 1.63-4.62) during the 4-week postvaccination period. Using the self-controlled case-series method, relative risk estimates during the 4-week postvaccination period were 3.02 (95% CI, 1.64-5.56) for all confirmed cases (n = 42) and 2.33 (95% CI, 1.19-4.57) for Brighton level 1 through 3 cases (n = 36). The number of GBS cases attributable to vaccination was approximately 2 per 1 million doses. There was no indication of an excess risk in persons younger than 50 years.

BC

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A great post BC.



One thing that concerns me about the major early vaccine candidates is they are all new approaches (and of course they are the early ones partly because more traditional approaches historically have taken longer). No mRNA vaccines have ever been through large human trials. Adenovirus vaccines have been around longer and tested in some trials, but none have passed FDA or European approval (the Chinese have approved some) AFAIK. I'm certainly no specialist in vaccines, but just that on it's face gives me a higher level of skepticism about both safety and efficacy.



Some articles that I've found infromative-



https://cen.acs.org/pharmaceuticals/vacc...-19/98/i19



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906799/

That's a fair concern.  I think the most mature technology (among the frontrunners) is probably the one from Novavax, and they have a partnership with CEPI, which should be reassuring.  This COVID-19 vaccine tracker from the NY Times is very good.

https://www.nytimes.com/interactive/2020...acker.html

Maryland-based Novavax makes vaccines by sticking proteins onto microscopic particles. They’ve taken on a number of different diseases this way; their flu vaccine finished Phase 3 trials in March. The company launched trials for a Covid-19 vaccine in May, and the Coalition for Epidemic Preparedness Innovations has invested $384 million in the vaccine. In July the U.S. government awarded $1.6 billion to support the vaccine’s clinical trials and manufacturing.

BC

[BostonCard]

What is considered acceptable, risk wise?  I’m talking in general for a vaccine?  And does that change in a pandemic?  In other words, is the acceptable risk increased a bit?

In general, because a vaccine is going into people that start out healthy, the tolerance for risk is going to be low, and the safety bar is going to be high.  That will probably change in the context of a pandemic, but there is still a fundamental problem which is that the people who harmed by a vaccine are easily identifiable (and some may even ascribe coincidental but unrelated ailments to the vaccine, as was the case with the MMR vaccine and autism), while the people who benefit are unidentifiable.  If you get vaccinated and don't get symptomatic coronavirus infection, you have no way of knowing whether that was because you got vaccinated or whether you would have been one of the many people who don't get symptomatic disease.

I do think that in the context of a pandemic, the safety bar ought to be relaxed a bit (within reason), as the number of people whose lives can be saved by a vaccine will number in the hundreds of thousands in the US alone, and the number harmed will be a lot lower even with a somewhat relaxed safety bar.  On the flip side, that has to be balanced against a small but vocal minority of people who are very distrustful of vaccines and could amplify their anti-vaccination message.  A vaccine that is ultimately deemed to be unsafe in the court of public opinion would be a disaster.  I wish it weren't so.

You can get an idea of what the safety bar has been historically from vaccines that have been withdrawn or restricted from the market for safety reasons:

For rotavirus:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462159/

The first rotavirus vaccine (RotaShield (Rotavirus, Live, Oral, Tetravalent – Wyeth)was licensed and recommended for routine use in the US by the Advisory Committee on Immunization Practices (ACIP) in 1998.5 This vaccine, was evaluated in 18,000 infants. A summary of the pre-licensing trials reported five cases of intussusception among 10,054 infants receiving vaccine and one case in 4,633 placebo patients (0.05% vs. 0.02%, P > .45). The FDA approved the vaccine on August 31, 1998, and the ACIP recommended routine use the following October for infants at age 2, 4, and six months. On July 16, 1999, the Vaccine Adverse Event Reporting Systems (VAERS) reported 15 cases of intussusception among recipients.6 The CDC placed a temporary suspension on routine administration until a case control investigation could evaluate these cases.7 This investigation demonstrated a strong relationship between RotaShield and intussusception, prompting the ACIP to withdraw its recommendation for routine use in October, 1999.8 The manufacturer voluntarily withdrew this product from the market shortly thereafter.

For dengue:
https://www.virology.ws/2017/12/07/a-pro...s-vaccine/

The numbers are small but significant. For example, during year 5 after the third dose of vaccine, 295 of 20,439 children (1.44%) were hospitalized with dengue virus infection. Severe dengue was also observed during years 2-4 after the third dose. Considering that millions of children will eventually receive this vaccine, serious disease occurring at a rate of 1.44% is not acceptable.

For H1N1 influenza:
https://jamanetwork.com/journals/jama/fu...le/1216476

Results Over a 6-month period, 83 confirmed GBS cases were identified, including 71 Brighton level 1 through 3 cases. Twenty-five confirmed cases had been vaccinated against 2009 influenza A(H1N1) 8 or fewer weeks before disease onset, with most (19/25) vaccinated 4 or fewer weeks before onset. In the Poisson model, the age- and sex-adjusted relative risk was 1.80 (95% CI, 1.12-2.87) for all confirmed cases during the 8-week postvaccination period and was 2.75 (95% CI, 1.63-4.62) during the 4-week postvaccination period. Using the self-controlled case-series method, relative risk estimates during the 4-week postvaccination period were 3.02 (95% CI, 1.64-5.56) for all confirmed cases (n = 42) and 2.33 (95% CI, 1.19-4.57) for Brighton level 1 through 3 cases (n = 36). The number of GBS cases attributable to vaccination was approximately 2 per 1 million doses. There was no indication of an excess risk in persons younger than 50 years.

BC

---

A great post BC.



One thing that concerns me about the major early vaccine candidates is they are all new approaches (and of course they are the early ones partly because more traditional approaches historically have taken longer). No mRNA vaccines have ever been through large human trials. Adenovirus vaccines have been around longer and tested in some trials, but none have passed FDA or European approval (the Chinese have approved some) AFAIK. I'm certainly no specialist in vaccines, but just that on it's face gives me a higher level of skepticism about both safety and efficacy.



Some articles that I've found infromative-



https://cen.acs.org/pharmaceuticals/vacc...-19/98/i19



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906799/

That's a fair concern.  I think the most mature technology (among the frontrunners) is probably the one from Novavax, and they have a partnership with CEPI, which should be reassuring.  This COVID-19 vaccine tracker from the NY Times is very good.

https://www.nytimes.com/interactive/2020...acker.html

Maryland-based Novavax makes vaccines by sticking proteins onto microscopic particles. They’ve taken on a number of different diseases this way; their flu vaccine finished Phase 3 trials in March. The company launched trials for a Covid-19 vaccine in May, and the Coalition for Epidemic Preparedness Innovations has invested $384 million in the vaccine. In July the U.S. government awarded $1.6 billion to support the vaccine’s clinical trials and manufacturing.

BC