Results from the AstraZeneca/Oxford Vaccine Trials
dalewharrison.substack.com
This is a longer article (about a 10-15 minute read) but contains some new and critically important information about how we can expect the vaccines to perform. Much of this will be counter-intuitive to the popular understanding of how vaccines work. I hope you are able to take the time to carefully read through the article…
The preliminary results from the Phase III trials of the AstraZeneca/Oxford Covid-19 vaccine were just published in the Journal Lancet. At a high level, the results closely mirror both the Pfizer and Moderna vaccine studies. The AstraZeneca vaccine is 90%+ effective at protecting against severe symptomatic illness.
But there are some really interesting additional data included in the study report that goes well beyond what was seen in the Pfizer and Moderna studies. Specifically, the very first data from human studies examining sterilizing immunity and some quite interesting data on re-infection rates.
TL;DR – the key findings in this area are:
The vaccine confers little or no protection from infection by the virus
Re-infection by the virus occurs at the same rate as first-time infections
These two findings point to some serious implications (discussed below):
No possibility of achieving herd immunity
Full endemic spread of the virus through the population
Potential to see the weekly death rate increase as vaccination levels increase!
I’ll explore each of these findings below, but first, let’s look at a quick summary of the key results of the AstraZeneca/Oxford vaccine trial…
Key Findings
11,636 participants were tracked over a 133-day period with a 90% vaccine efficacy against moderate-to-severe symptomatic disease. There was a high incident of short-term moderate-to-severe adverse reactions, but none that represented any health threat. There were no adverse effects that represented serious health or safety issues.
There is no information on duration beyond the 2-months of protection also seen in the other vaccine trials. These vaccines almost surely have a longer duration, likely 6-12 months, but due to the brief length of the trial, this is all the data available.
These results are nearly identical to what has been reported out of both the Pfizer and Moderna mRNA vaccine studies and show a potential 3rd highly effective vaccine candidate. This is very good news!
Vaccine Technology
This vaccine is a viral-vector type vaccine, a different vaccine technology than the Pfizer and Moderna mRNA vaccines. It is a recombinant replication-defective chimpanzee Ad5-adenovirus expressing the SarsCoV2 S-gene.
Essentially a chimpanzee adenovirus (Ad5 strain) that’s been genetically altered to prevent the virus from replicating, with additional genes inserted designed to produce copies of the SarsCoV2 spike-protein once the adenovirus has been injected and infects host cells.
One issue with this technology is those receiving this vaccine will develop an immune response to the chimpanzee adenovirus, rendering the virus unusable for future re-vaccinations. You literally develop an immune response against the vaccine itself in addition to SarsCov2. These chimpanzee adenovirus vaccines will also not be effective in sub-Saharan Africa due to the high prevalence of exposure to chimp adenovirus strains.
These are issues unique to viral-vector vaccines and not expected to a problem with the mRNA vaccines from Pfizer and Moderna.
No Sterilizing Immunity
Now for the interesting part of the study. This is the ONLY vaccine trial where participants were tested for SarsCoV2 infection on a weekly basis throughout the trial. That makes this the sole look at whether these SarsCoV2 vaccines are able to confer sterilizing immunity.
Sterilizing immunity is the ability of a vaccine to prevent infection and re-transmission of the virus. This is completely independent of “disease immunity” which measures how well the vaccine reduces symptomatic disease. So far, the prior vaccine trials have explicitly avoided looking at sterilizing immunity.
Sterilizing immunity is a feature of some vaccines such as the measles and HPV vaccines, but is lacking or entirely absent in others, such as the seasonal influenza vaccine.
The Data
The study was split into two sections based on vaccine dosage. One group received a lower dosage initially (LD) and then a larger standard dosage (SD) 3-weeks later. The other group received the larger standard dosage for both injections. Both the vaccine and placebo arms of the trial were then tested weekly for asymptomatic infection by the SarsCoV2 virus.
For those receiving the standard SD/SD protocol, the rate of asymptotic infection was identical between the vaccinated group and the placebo group. Zero sterilizing immunity.
For those receiving the modified LD/SD protocol, the rate of asymptomatic infection within the vaccine group was more than 40% that of the placebo group. Partial ineffective sterilizing immunity.
In addition, of the 66 total cases of infection in the vaccine group, 29 of these were asymptomatic, or 44%. This closely matches data from Moderna’s study.
In the just-released VRBPAC Report on the Moderna vaccine trials, they found a similar ~40% rate of asymptomatic infection. In the case of the Moderna trial, they only tested for infection at the time of each injection 28 days apart. So a less systematic study than AstraZeneca, but with nearly identical outcomes.
To summarize:
SD/SD dosage, equal asymptomatic infection rates between vaccine and placebo groups
LD/SD dosage, vaccine group had asymptomatic infection at 40% of the rate of the placebo group
44% of all infections in the AstraZeneca vaccine group were asymptomatic infection
~40% of Moderna vaccine recipients developed asymptomatic infection between the 1st and 2nd dosage
Evidence suggests that both the AstraZeneca and Moderna vaccines provide only limited sterilizing immunity with a post-vaccination asymptomatic infection rate at roughly half the level of the non-vaccinated population.
This is NOT an unexpected outcome. The early animal vaccine trials back in April and May 2020 with the Pfizer, Johnson & Johnson and AstraZeneca vaccines demonstrated no effective sterilizing immunity in either transgenic mice (genetically engineered mice designed to look like humans to the virus) or in rhesus monkey studies.
From the Lancet paper:
”Asymptomatic infections or those with unreported symptoms were detected in 69 participants. Vaccine efficacy in the 24 LD/SD recipients was 58·9% (95% CI 1·0 to 82·9), whereas it was 3·8% (−72·4 to 46·3) in the 45 participants receiving SD/SD”
From the article in the Journal Nature:
“Another lingering question is whether the vaccine is capable of fighting asymptomatic infections; an immunization that could do that could be key to shaping the course of the pandemic.”
”The data show that the low-dose vaccine regimen was about 60% effective at reducing asymptomatic infections, but it is unclear whether the standard dose significantly reduced them at all.“
“Researchers are concerned about asymptomatic infections because people who have them might unknowingly continue to transmit the virus to others, despite being vaccinated. “
“For now, this is the only study that’s given us data on that,” says Griffin. “And it’s a bit troubling.”
Implications of No Effective Sterilizing Immunity
Lack of effective sterilizing immunity means that asymptomatic infections will allow the continued spread of the virus, despite being vaccinated.
There are a few immediate implications to this lack of effective sterilizing immunity:
There is no possibility of ever achieving herd immunity
The virus will likely go fully endemic with widespread asymptomatic spread
The entire population must be vaccinated or face an extremely high likelihood of unprotected serious Covid-19 illness.
Masking, distancing, and other mitigation measures will have to remain in effect indefinitely to avoid infection and illness, even for vaccinated.
Because vaccinated individuals are only protected from severe symptomatic illness, but not from infection or mild-to-moderate illness, there will need to be efforts to avoid transmission. Especially until at least 90% of the population has been vaccinated.
The SarsCoV2 virus is an extraordinarily contagious virus. We have seen nothing in widespread transmission this contagious in 60 years. Not since widespread measles was eliminated in the early 1960s with the introduction of the measles vaccine. Because the measles vaccine conferred sterilizing immunity we were able to achieve effective herd immunity with only isolated outbreaks among those refusing vaccination.
SarsCoV2 is significantly more contagious than seasonal influenza and quite a bit more contagious than the common cold. We typically see about 40-60 million flu cases a year but over 1 billion colds each year. The average American gets 3 colds a year with ~93% of the population contracting at least one cold a year.
Without ongoing mitigation efforts and with the ability of the virus to continuously re-infect (see the next section), when this virus goes fully endemic, we should expect to see infection rates comparable to the common cold. But with Covid-19 mortality rates likely comparable to seasonal influenza (due to the effective reduction in severe illness once infected).
As common as the cold…as deadly as the flu.
Without ongoing mitigation efforts, this will be a DEADLY combination! Without continued efforts to reduce the spread of the virus, we could actually see the weekly death rate increase as vaccination levels increase. If the death rate drops by a factor of 10x (likely given the efficacy of the vaccines at reducing severe illness), but the overall infection rate rises by 10x or 20x, we would see death rates as high or higher than what’s currently being experienced.
Given the lack of good public health messaging around these issues and the intense political pressure to drop all mitigation requirements once widespread vaccination programs are in place, I fully expect just such an outcome.
If that happens, then SarsCoV2 will become the 3rd leading cause of death in the US for at least the next several years with annual fatality rates in the range of 300,000 to 400,000 per year. Covid-19 deaths will be exceeded only by heart disease and cancer.
Eventually, there will be therapeutics that should reduce the fatality rate, but even then the ongoing load on the health care system will be significant for years to come.
Re-Infection Occurs at the Same Rate as Initial Infection
Now for the second piece of VERY interesting data buried in the study.
All the other vaccine studies attempted to exclude people who had previously been infected. Potential study subjects were screened for seropositivity, meaning they had antibodies from a prior Covid-19 infection. The AstraZeneca study tested for seropositivity but included all these subjects directly into the vaccine study.
And because the AstraZeneca study included weekly testing for infection, this set up an interesting situation where previously infected people could be monitored for re-infection. And this re-infection rate could be compared to the initial infection rate seen in the placebo group.
There were 138 people in the seropositive group (previously infected with Covid-19). Of those, 3 were re-infected during the 4-month period of the study or just over 2%.
Of the 5,829 people in the placebo control group, 101 were infected during the 4-month study period or just under 2%.
These absolute numbers are low, but that has to be seen in the light of the small sample size (10,000 people) and the short duration of the study (~4 months).
Although the absolute numbers are small, this points to two key findings:
Re-infection is possible and not a rare event (otherwise there would have been none in such a small short-duration study)
The risk of re-infection is approximately equal to the risk of initial infection
This is entirely unsurprising given what’s understood about the short duration of immune protection from natural infection and the behavior of all other known corona-like viruses to re-infect (the average person gets 3 colds a year). But it’s nonetheless interesting to see this result drop out of a well-designed and well-controlled study.
Concluding Thoughts
Although these findings are quite counter-intuitive to the popular notions of how vaccines work, such outcomes are not uncommon for many types of vaccines.
As many as half of those who get the seasonal influenza vaccine will be infected, many as asymptomatic carriers of the flu virus. This is a key underlying mechanism behind what experts mean when they talk about the seasonal influenza vaccine being 10% to 40% effective. Although you are somewhat protected against severe illness, a large portion of those with the flu vaccine can and will still get infected each year.
So these outcomes are neither entirely unexpected. I first started writing about the risk of re-infection back in mid-February and I have been writing about the potential lack of sterilizing immunity since mid-June when the first vaccine animal studies showed identical infection rates between vaccinated and non-vaccinated animals during challenge trials (where the animals are deliberately exposed to the virus).
But the public policy implications are significant. If mitigation measures are discouraged or dropped, especially before reaching vaccination levels of 90% or more, we risk dramatically expanding the scope and lethality of the epidemic.
Companion Video
This is a short (4-minute) video of a segment from “This Week in Virology” where the co-hosts discuss the data from the AstraZeneca report and the implications of no effective sterilizing immunity.
It’s interesting to see how these concepts can be confusing and counter-intuitive, even for virologists who are actively involved in Covid and SarsCoV2 research.
I am a scientist with 20+ years in the biotech industry. I currently work as a consultant with companies involved in developing molecular diagnostics platforms, including some of the key testing platforms used to detect the SarsCoV2 virus.
So I bring an insider’s perspective that is scientifically oriented but directed to a general audience trying to make sense of the conflicting stories surrounding the Covid pandemic.
This was the most detailed and interesting article (and podcast with Mark Hyman) that I have seen and was hugely helpful. I only listened to it yesterday, just before my partner received the AstraZeneca vaccine. His doctor said that it was 95% effective against ALL covid infections and asymptomatic transmission, even when I checked with her. I saw that there has been another very recent study coming out of Israel in the last day or so, suggesting these type of results. How can there be such a disparity between the same vaccine studies? If we take this latest data, it would suggest no reason for many mitigation practices, which living here in the UK with the new variant, concerns me hugely.
thanks for the piece. is the pfizer/moderna vaccine that is out in the US protect from asymptomatic contraction/illness?
This was the most detailed and interesting article (and podcast with Mark Hyman) that I have seen and was hugely helpful. I only listened to it yesterday, just before my partner received the AstraZeneca vaccine. His doctor said that it was 95% effective against ALL covid infections and asymptomatic transmission, even when I checked with her. I saw that there has been another very recent study coming out of Israel in the last day or so, suggesting these type of results. How can there be such a disparity between the same vaccine studies? If we take this latest data, it would suggest no reason for many mitigation practices, which living here in the UK with the new variant, concerns me hugely.