[lex24]

Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.

That's not the safety profile of a vaccine that gets approved.  At the very least, the 250 µg dose is toast, but even the 100 µg dose, 100% of the volunteers reported a systemic adverse event after the second dose (80% of the volunteers had a moderate adverse event).  Even the lowest dose, more than 50% of volunteers had a systemic adverse event (25% moderate intensity).  Even more had local symptoms.



The good news is that even the lowest dose produced immunogenicity.  Moderna should have explored a lower dose, since the immunogenicity was pretty strong even at 25 µg.  I think they are making a mistake in looking at 50 and 100 µg in the phase 2 trial (and planning for 100 µg in a phase 3).  Yes, there is a question is how long immunity will last at the lower doses, but honestly I think the safety of the vaccine is going to be the problem.



BC

I haven't looked at the data, but I assume no one died or had a life-threatening  response to the vaccine.   I also assume that the study population was relatively healthy.  Does a large number of adverse events in a trial mean that if you gave the vaccine to everyone, some people would die? I.e., are the symptoms seen in the trial the tip of the iceberg so to speak, and the actual response in the entire population would be a lot worse?

Or is the problem just that headaches, etc. might reduce vaccine acceptance or create problems with loads of vaccinated people showing up at doctors' offices to get their symptoms checked?

It doesn't always work that way, but the concern would be that if a large proportion of patients in a small study develop moderate adverse events, a small but non-zero proportion of patients in a larger study will develop more severe adverse events, and a few patients in a very large study (or once it goes to market) will develop life-threatening adverse events (or even die).

When the first H1N1 swine flu vaccine came out, it eventually had to be recalled because a small but significant increase in the risk of a very rare adverse event (Guillain-Barré Syndrome) which can cause paralysis.  The increased risk over baseline was just 1.6 excess cases of Guillain-Barré syndrome per million people vaccinated, but for a person who is healthy, that is a devastating and unacceptable adverse event.  A couple other vaccines that have had to be recalled because they caused rare side effects was the rotavirus vaccine (This additional risk is estimated to range from about 1 in 20,000 to 1 in 100,000 US infants who get rotavirus vaccine.). The other one (and this scares me about the COVID-19 vaccines) is dengue, which was severely restricted after potentially causing fatal ADE (antibody dependent enhancement, where the disease is actually worse in patients who are vaccinated) in 2 in 10,000 children.

BC

What is considered acceptable risk?  If I understand you correctly (and I probably don’t) you are saying a vaccine that had an increased risk of a serious disease for 1.6 out of a million people is considered unacceptable.  Is that true?

[lex24]

Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.

That's not the safety profile of a vaccine that gets approved.  At the very least, the 250 µg dose is toast, but even the 100 µg dose, 100% of the volunteers reported a systemic adverse event after the second dose (80% of the volunteers had a moderate adverse event).  Even the lowest dose, more than 50% of volunteers had a systemic adverse event (25% moderate intensity).  Even more had local symptoms.



The good news is that even the lowest dose produced immunogenicity.  Moderna should have explored a lower dose, since the immunogenicity was pretty strong even at 25 µg.  I think they are making a mistake in looking at 50 and 100 µg in the phase 2 trial (and planning for 100 µg in a phase 3).  Yes, there is a question is how long immunity will last at the lower doses, but honestly I think the safety of the vaccine is going to be the problem.



BC

I haven't looked at the data, but I assume no one died or had a life-threatening  response to the vaccine.   I also assume that the study population was relatively healthy.  Does a large number of adverse events in a trial mean that if you gave the vaccine to everyone, some people would die? I.e., are the symptoms seen in the trial the tip of the iceberg so to speak, and the actual response in the entire population would be a lot worse?

Or is the problem just that headaches, etc. might reduce vaccine acceptance or create problems with loads of vaccinated people showing up at doctors' offices to get their symptoms checked?

It doesn't always work that way, but the concern would be that if a large proportion of patients in a small study develop moderate adverse events, a small but non-zero proportion of patients in a larger study will develop more severe adverse events, and a few patients in a very large study (or once it goes to market) will develop life-threatening adverse events (or even die).

When the first H1N1 swine flu vaccine came out, it eventually had to be recalled because a small but significant increase in the risk of a very rare adverse event (Guillain-Barré Syndrome) which can cause paralysis.  The increased risk over baseline was just 1.6 excess cases of Guillain-Barré syndrome per million people vaccinated, but for a person who is healthy, that is a devastating and unacceptable adverse event.  A couple other vaccines that have had to be recalled because they caused rare side effects was the rotavirus vaccine (This additional risk is estimated to range from about 1 in 20,000 to 1 in 100,000 US infants who get rotavirus vaccine.). The other one (and this scares me about the COVID-19 vaccines) is dengue, which was severely restricted after potentially causing fatal ADE (antibody dependent enhancement, where the disease is actually worse in patients who are vaccinated) in 2 in 10,000 children.

BC

What is considered acceptable risk?  If I understand you correctly (and I probably don’t) you are saying a vaccine that had an increased risk of a serious disease for 1.6 out of a million people is considered unacceptable.  Is that true?