AFFIRMATION COMPLETE: “Data from highly vaccinated countries suggests strongly that the answer is yes; vaccinated people are at higher risk of infection from Omicron”; “Danish researchers [...] found protection against Omicron turned negative three months after the second dose”; “And what about the real terror, antibody-dependent enhancement?”
REVIEW
A Substack article written by journalist Alex Berenson claimed that “vaccinated people are at higher risk of Omicron”, citing a study conducted by researchers in Denmark. The article received more than 2,500 user engagements on Facebook, including more than 1,100 shares. The same claim was also made by U.S. Senator Rand Paul on Fox News, as can be seen in this TikTok video that was shared more than 106,000 times.
The study in question is a preprint, which is a study that hasn’t been peer-reviewed by other scientists yet, authored by a team of researchers at Statens Serum Institut. Its aims were to examine the level of protection from vaccination with COVID-19 mRNA vaccines against Omicron infection and track the waning of vaccine effectiveness over time[1]. The researchers used Danish nationwide registries to extract data on COVID-19 PCR test results and vaccination status for Danish residents aged 12 and above.
Health Feedback reached out to the preprint’s authors for comment. The first author, medical statistician and epidemiologist Christian Holm Hansen, refuted the claim, stating that the “Interpretation that our research is evidence of anything but a protective vaccine effect is misrepresentative”. [see his full comments below]
He also explained why vaccine effectiveness (VE) was observed to be negative in the study, citing the presence of bias in the VE estimates, saying that “Such biases are quite common in VE estimation from observational studies based on population data”, unlike in phase III clinical trials. Indeed, a preprint published by scientists in Ontario, Canada, which also examined vaccine effectiveness in an observational study and detected negative vaccine effectiveness[2], was found to have been “influenced by behavioural and methodological issues, such as the timing of the observational study, the way in which vaccine passports altered individual risk and changes in access to COVID-19 testing”. That preprint is currently being revised.
Hansen offered several reasons for how bias could occur in a study. For example, he pointed out that vaccinated individuals tend to get tested more often than unvaccinated people. Another reason could have to do with the fact that Omicron cases by and large were detected in international travelers, most of whom were vaccinated. “We expect therefore that there was an overrepresentation of vaccinated people among the first generations of Omicron cases identified in Denmark, not because the vaccines weren’t protective, but because the variant hadn’t spread far enough into the general population, including into the unvaccinated population, to make for comparable infection rates,” he said.
Indeed, the preprint concluded in favor of vaccination, not against it:
« Our study contributes to emerging evidence that BNT162b2 or mRNA-1273 primary vaccine protection against Omicron decreases quickly over time with booster vaccination offering a significant increase in protection. In light of the exponential rise in Omicron cases, these findings highlight the need for massive rollout of vaccinations and booster vaccinations.«
Berenson also claimed that there was “the real terror [of] antibody-dependent enhancement” from vaccination. Antibody-dependent enhancement, or ADE for short, occurs when antibodies against a virus improve the virus’ ability to cause infection, rather than impede it. Contrary to the impression given in Berenson’s article, ADE can arise as a result of antibodies from a previous infection or vaccination, as we see in cases of dengue fever. The phenomenon isn’t exclusive to vaccination.
Antibody-dependent enhancement manifests as severe illness. If vaccination made people more prone to severe illness, we would have seen a higher incidence of severe COVID-19 in vaccinated people compared to unvaccinated people. Instead, we observe the opposite: vaccinated people are less likely to develop severe COVID-19 compared to unvaccinated people[3-5]. This is evidence that vaccination isn’t leading to ADE.
In summary, claims that the preprint is evidence the vaccines make people more prone to illness are inaccurate and misrepresent the researchers’ findings. Scientific evidence so far indicates that COVID-19 vaccination continues to provide people with a high level of protection against severe illness and death, even in the face of the Omicron variant. Vaccination can also reduce a person’s risk of infection to some extent, although this protection is less effective against the Omicron variant compared to earlier reported variants. However, a booster dose can help to bolster waning immunity.
SCIENTISTS’ FEEDBACK
Interpretation that our research is evidence of anything but a protective vaccine effect is misrepresentative.
The aims of the study were to:
(a) determine whether there was any evidence of vaccine protection against Omicron infection after a primary vaccination series and booster vaccination with either the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines.
(b) investigate evidence of waning vaccine effectiveness over time.
So what did we see?
Our study provides evidence of protection against infection with the Omicron variant after completion of a primary vaccination series with the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines in the first months after primary vaccination. However, the VE is significantly lower than that against Delta infection and declines rapidly over just a few months. The VE is re-established upon revaccination with the BNT162b2 vaccine.
To expand a little more on this, the protection is strongest in the months immediately after vaccination with an estimated vaccine effectiveness of around 55% for the Pfizer vaccine. A vaccine effectiveness of 55% broadly means that you are 55% less likely to get infected if you’re vaccinated than if you’re not.
Regarding negative vaccine effectiveness:
The research shows early results from the first 20 days of Omicron in Denmark. The fact that the estimated VE is negative during the last period suggests that there is bias in the comparison between the vaccinated and the unvaccinated population. We also make this point in the discussion.
If a study estimate is biased it means that it is measuring something different from what was intended. The VE estimate may be biased if the infection rates in the vaccinated and unvaccinated populations are impacted by effects other than the vaccines.
Such biases are quite common in VE estimation from observational studies based on population data (unlike a phase 3 randomised trial which is the gold standard).
There are a number of reasons why the VE estimate might be negative.
- In many places including Denmark, vaccinated individuals are tested more frequently than unvaccinated individuals. This causes the incidence rate to be higher in the vaccinated population and resultantly a negative VE estimate.
- Denmark was very quick to conduct sequencing and to identify the first generations of Omicron cases in the country. Cases during this period occurred to an exaggerated extent in those who were travelling internationally, and those in the social and professional circles of travellers, and were largely vaccinated. We expect therefore that there was an overrepresentation of vaccinated people among the first generations of Omicron cases identified in Denmark, not because the vaccines weren’t protective, but because the variant hadn’t spread far enough into the general population, including into the unvaccinated population, to make for comparable infection rates.
- VE estimation relies on vaccinated and unvaccinated individuals behaving in a similar fashion in their everyday lives with respect to COVID-19 precautions and exposure to infection risk. It is conceivable that the increasingly small cohort of unvaccinated individuals that remains in Denmark takes further precautions (precisely because they are not well-protected), engage less in social activities, etc. Such discrepancies in risk behaviour between vaccinated and unvaccinated individuals will lead to an underestimated VE.
On that basis it is reasonable to expect that the vaccine effectiveness estimates presented in our study are too low.
To conclude, the vaccines’ protective effect may be low against infection with Omicron after four months, but it is most unlikely to be negative!
I should also point out that our research is not yet peer-reviewed. This is the process where other scientists, epidemiologists assess the work for its rigour and robustness.
REFERENCES
- 1 – Hansen et al. (2021) Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study. medRxiv. [Note: This is a preprint that has not yet been peer-reviewed.]
- 2 – Buchan et al. (2022) Effectiveness of COVID-19 vaccines against Omicron or Delta infection. medRxiv. [Note: This is a preprint that has not yet been peer-reviewed.]
- 3 – Scobie et al. (2021) Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status — 13 U.S. Jurisdictions, April 4–July 17, 2021. Mortality and Morbidity Weekly Report.
- 4 – Andrews et al. (2022) Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines. New England Journal of Medicine.
- 5 – Chung et al. (2021) Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study. BMJ.
