The development of vaccines may well go down as the finest demonstration of the power of our understanding of bio-science to date. Its not just the speed of development , its the basis in molecular biology.
Vaccine decision - extract of an NY Times opinion piece by Natalie Dean is an assistant professor of biostatistics
at the University of Florida.
Coronavirus vaccines are rapidly advancing through the development pipeline. The University of Oxford’s vaccine is in
large trials in Britain, Brazil and South Africa. In the United States, researchers just began enrolling around 30,000
volunteers to test Moderna’s vaccine, and more trials are starting every day. Operation Warp Speed has set an
ambitious goal of delivering 300 million doses of a safe, effective vaccine by January.
While there is promising data from smaller trials that measured the antibody response in people who got a vaccine, it’s
not enough to approve a vaccine. We don’t know the level of antibodies needed to prevent infection from this virus.
There is a history of vaccines with promising immune response data that did not pan out in the field.
How many people need to be protected by a vaccine before it’s recommended for widespread use? Ideally, rates of
disease will be 70 percent lower in vaccinated people than in unvaccinated people. The World Health Organization says
a vaccine should be at minimum 50 percent effective, averaged across age groups. (We know from influenza that
vaccines don’t always work as well on older adults whose immune systems have declined.)
This benchmark is crucial because a weak vaccine might be worse than no vaccine at all. We do not want people who
are only slightly protected to behave as if they are invulnerable, which could exacerbate transmission. It is also costly to
roll out a vaccine, diverting attention away from other efforts that we know work, like mask-wearing, and from testing
The last thing Phase III trials do is examine safety. Earlier trials do this, too, but larger trials allow us to detect rarer side
effects. One of those rare effects researchers are paying attention to is a paradoxical phenomenon known as immune
enhancement, in which a vaccinated person’s immune system overreacts to infection. Researchers can test for this by
comparing the rates of disease severe enough to require hospitalization across the two groups. A clear signal that
hospitalization is higher among vaccinated participants would mark the end of a vaccine.
A key to getting a quick result is placing the trial in outbreak hot spots where people are most likely to be infected. We
can even target the highest-risk people within those areas, using mobile teams to travel to neighborhoods, bringing the
trial directly to the people. Some trials explicitly prioritize essential workers like health care workers or grocery
employees. Others are simply focused on enrolling large numbers of participants as fast as possible. Combining those
efforts, it could take as little as three to six months to generate enough convincing safety and efficacy data for
companies to apply for expedited review by the Food and Drug Administration.
I worry nonetheless that public pressure may mount to approve a product that doesn’t meet our standards. Other
countries may decide to approve vaccines based on weaker evidence. Russia, for example, claims to be on track to
approve a vaccine in just a few weeks.
Waiting for a better vaccine to come along may feel like torture, but it is the right move. With so many potential shots on
goal, scientists are optimistic that a safe and effective vaccine is out there. We can’t afford to jeopardize the public’s
health and hard-earned trust by approving anything short of that."
Now that vaccine hype is off and running, I wondered what should be a realistic expectation.? According to https://www.
healthline.com/health/clinical-trial-phases…“Phase III of a clinical trial usually involves up to 3,000 participants who have
the condition that the new medication is meant to treat. Trials in this phase can last for several years.” Randomly, half
get the placebo and half the test medication. In the case of a vaccine, the phase 3 trial involves 30,000 volunteers,
started in August, with initial results by beginning of Dec after 4 months.
The current infection rate in the US is around 100 per day per million, on the average in the placebo half of the trial
population, 1.5 per day will get infected. Over the 4 months trial , about 200 will get develop symptoms, about 40 will go
to hospital, and about 2 will die. Meanwhile, there will be a background level of hospitalizations and deaths that happen
all the time, on the average over the 4 month in a random sample of 15,000, around 40 will end up in hospital.
My simple minded conclusion, is that at the end of the 4 month trial, we should know if the vaccine produced antibodies
as they will be testing everyone. We might know something about reducing symptoms based on a sample size of 200,
not much about hospitalizations based on a placebo sample size of 40 on a background of 40 and nothing about
fatalities based on a sample size of 2 on a background of 50. To get to the trial population for a typical medication, we
need to wait roughly a year and a half for 3000 placebo trial participants to show symptoms.
Fishing boat study shows antibodies protecting against infection - small study 8/2020
Three crew of a Seattle fishing boat who were found to have antibodies able to neutralise the new coronavirus remained
uninfected in an outbreak that swept through the ship, sickening most people on board, researchers have reported.
Researchers screened 120 of 122 people before they boarded the fishing vessel in May, testing both for active virus
and for antibodies in the blood that would indicate a previous or ongoing infection.
None of the crew tested positive for the virus, but six had some antibodies and of those, three had evidence of
More than two weeks after the boat set sail, it returned to shore with an infected crew member who needed hospital
treatment. They found that 85 percent—104 crew members—were infected.
But none of the three with neutralising antibodies tested positive, nor did they report any symptoms during the outbreak.
"Therefore, the presence of neutralising antibodies from prior infection was significantly associated with protection
against re-infection," the authors of the study said.
Mild Covid gives immunity 5/2020
Even people with minor illness from the coronavirus can develop antibodies that could leave them immunised for several
weeks or more, according to an early French study that tested hospital staff with mild infections.
The study was carried out on 160 members of staff at two hospital sites in Strasbourg who had all tested positive for
COVID-19 and suffered mild forms of the disease. Two types of serological tests, which aim to look for a previous
infection, indicated that almost all health workers—153 out of 160 in one case, 159 out of 160 in the other—had
developed antibodies within 15 days after the onset of infection. Using a separate test to determine if the antibody could
neutralise the virus, the study found some 98 percent of the volunteers had these antibodies between 28 and 41 days
after the first signs of infection.
The researchers said in a statement on Tuesday that the neutralising activity of the antibodies appeared to increase
Vaccine trial status 10/29/20
The experts (see the links below) are making it clear what is expected from the current vaccine trials - information on
whether the vaccine reduces infections, but nothing about reduction of hospitalizations or deaths, the sample size is just
to small. The Pfizer vaccine trial started July 28 and involved 44,000 volunteers. By October 27, they announced that
they were almost fully enrolled and had not yet reached 32 infections. Apparently, once they reach 32 infections, an
independent panel reviews the data to make a first assessment of the vaccine, with a final goal of 100 infections to
analyze. A cold and a positive test qualifies as an infection.
The trial has started 3 month ago, and is only just fully populated so lets assume they have had an average of 22,000
volunteers for the test period up till now. The current infection rate in the US is around 100 per day per million. In the 3
months of the trial, if the vaccine is working there should have been around 100 infections in the placebo group. So
either the average number of volunteers is lower, or they are being more careful and not getting infected. Either way, we
still have to wait before any conclusions can be made.
It is probably worth noting that 32 infections is a pretty small number to base any conclusions. In an article an editor at
BMJ stated “Like Pfizer and Johnson and Johnson, Moderna has designed its study to detect a relative risk reduction of
at least 30% in participants developing lab-confirmed COVID-19, consistent with FDA and international guidance.”
In addition "None of the trials currently underway are designed to detect a reduction in any serious outcome such as
hospitalisations, intensive care use, or deaths. Nor are the vaccines being studied to determine whether they can
interrupt transmission of the virus,"
This makes sense, because we have a Case Fatality Rate of about 2% at the moment so no one should have died in
either group, and so they cannot tell if the vaccine is safer than getting Covid based on this sample size. The test would
need to be at least much longer or larger to draw any safety conclusions. Ironically. the more effective the vaccine, the
more difficult it is to know if the vaccine makes the results of infection better or worse. When you plan to vaccinate 300M
people, it is a critical question.
Vaccine update 11/11/20
Terrific news on the vaccine front, Pfitzer reports that their vaccine was “at least 90% effective”, based on 98 infections
in the Phase 3 trial. A political opinion poll is based on around 1000 interviews, and as we know, are not very accurate.
We should be encouraged but cautious in drawing conclusions from a sample 1/10 of an opinion poll. The data is not
yet public , assuming that Pfitzer have been appropriately conservative in their announcement, “at least 90% effectivity”
based on a sample of 98 means that at most 1 or 2 people in the treatment group became infected. As a result we know
nothing about any possible side effects of being vaccinated and then getting infected.
Very encouraging early results.
Vaccine update 11/18/20
The Moderna and the Oxford vaccine show similar success, suggesting that Covid is an infection that can be blocked by vaccination. It sounds like Q1 is a realsitic target for wide availability.
There is more data on the Pfitzer, the high lights from their press release (not a paper !) are;
Primary efficacy analysis demonstrates BNT162b2 to be 95% effective against COVID-19 beginning 28 days after the first dose;170 confirmed cases of COVID-19 were evaluated, with 162 observed in the placebo group versus 8 in the vaccine group
Efficacy was consistent across age, gender, race and ethnicity demographics; observed efficacy in adults over 65 years of age was over 94%
Safety data milestone required by U.S. Food and Drug Administration (FDA) for Emergency Use Authorization (EUA) has been achieved
Data demonstrate vaccine was well tolerated across all populations with over 43,000 participants enrolled; no serious safety concerns observed; the only Grade 3 adverse event greater than 2% in frequency was fatigue at 3.8% and headache at 2.0%
Companies plan to submit within days to the FDA for EUA and share data with other regulatory agencies around the globe
The companies expect to produce globally up to 50 million vaccine doses in 2020 and up to 1.3 billion doses by the end of 2021
Really good news, but please note that a sample of 162 infected persons is 10x lower than a typical opinion poll ! These numbers will change and who knows in which direction.
11/30/2020 Vaccine update
Moderna has gone public with their data and have applied for emergency use. The results were;
11 of 15,000, none became seriously ill.
185 out of 15,000 in placebo.
Very similar results to Pfitzer, which is encouraging as Moderna and Pfitzer use the same approach.
12/14/20 EUA submission and approval for Pfitzer
The submissions to the FDA for EUA are public documents. Here are a few extracts from an analysis of those docs.
"The FDA briefing docs also highlighted how important it will be for patients to come back for a second dose. The phase 3 trial revealed that the vaccine was only 52% effective in the three weeks between the first and second dose, the analysts noted. Efficacy skyrocketed to nearly 95% a week after the second dose.
One major point of discussion at the meeting—where vaccine experts will offer their approval advice to the FDA—will be side effects that cropped up in the phase 3 trial, analysts predicted. The side effects were rare but inflammatory in nature. For example, there were more cases of appendicitis and Bell’s palsy among those who received the vaccine than in the placebo group.
Pfizer is planning three post-authorization surveillance studies, according to the briefing package (PDF). And the FDA will also have access to data gathered from a new Centers for Disease Control smartphone app called v-safe. Vaccine recipients will be able to opt-in to v-safe and use it to report any side effects.
J.P. Morgan analysts concluded that side effects reported in the trial wouldn't scuttle Pfizer’s emergency use authorization (EUA), because the stats lined up with numbers typical in the general population. The incidence of Bell's palsy, a type of facial paralysis, matched up with typical experience, the FDA said, though there were no cases reported in the trial's placebo group.
SVB Leerink analysts picked out another detail in the Pfizer briefing document: The previous infection offered just 37% protection against re-infections with symptomatic COVID-19. Granted, only seven cases of re-infection were reported in the trial, but the revelation that getting sick with COVID might not protect people from catching the virus again could be significant, the analysts said."
The conclusion is that there may be subtle differences in side effect between vaccines.... and of course the sample size is really small, but will get bigger quickly.