Concern about Covid-19 vaccine efficiency related to biased analyses not captured by the review process Re: Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study
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Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study
Concern about Covid-19 vaccine efficiency related to biased analyses not captured by the review process Re: Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study
Dear Editor,
We read with interest the paper by Lisa Lundberg-Morris, et al. (1) which reviewed the Covid-19 vaccine effectiveness against post-covid-19 condition in a population-based cohort in Sweden of 589 722 individuals. It raises a number of significant concerns in the analyses conducted and its conclusions. This paper analyses two cohorts. Cohort A: not vaccinated prior to having Covid-19; cohort B: vaccinated prior to having Covid-19.
The first observation relates to the death ratio in cohort A (0.28%, 821/290030) which is significantly lower (p=0.001) than in cohort B (0.36%, 1076/299692). The risk of death is in fact the most important, while the other items can be qualified as intermediate criteria.
In addition, neutralizing and facilitating antibodies may be produced against the virus. The modeling work published by Yahi et al. shows that antibodies facilitating the spread of the virus (ADE) have more affinity with the spike protein than neutralizing antibodies in regard to the delta variant (on the contrary to what is observed with the original strain of SARS-CoV-2 of 2020, Wuhan/D614G) (2). The appearance of a given variant may thus favour the ADE phenomenon, and could explain why the vaccine (developed from the first strain of the virus) can be deleterious in certain cases. As a matter of fact, 59 349 individuals were excluded from the analysis because events occurred less than 28 days of Covid-19 index date (56 760 vaccinated, 2515 died, 74 emigrated). The reason for exclusion was vaccination for 56 760 patients and death for 2515. The cause of death is unknown and should have been analysed. We do not know how many of these patients were vaccinated. This intermediate group should have been analysed to model the trend or adapt the less than 28 days of covid-19 index date exclusion.
The third observation is related to a cohort bias as cohort A has been exposed to different variants compared to cohort B. 60.2% of persons in cohort A had a variant Alpha predominant during acute infection versus 3.5% in cohort B. And cohort B had variant Omicron predominant at 74.9% vs 12.4% for cohort A.
Populations are heterogenous and cannot be compared as they are not exposed to the same variants, each of which has a different morbidity and lethality. Indeed, Liu Y et al. reported that infection fatality ratio of Omicron variant was reduced by 78.7% (95% confidence interval: 66.9%, 85.0%) with respect to previous variants (3). In Lisa Lundberg-Morris, et al.’s study, the vaccinated population (Cohort B) was predominantly exposed to much more benign variants than the unvaccinated population (Cohort A).
Vaccination effectiveness against post covid-19 condition should thus have been done by variant to cope for the different fatality ratio by variant. This bias, which is of crucial importance, is not mentioned in the limitation of the study.
Last but not least, the risk of infection was higher with the higher number of vaccine doses, which should have been discussed (4). Variant matching is essential to draw a reliable conclusion about vaccine efficacy.
Altogether, we raise serious concerns about the analytical choices made for the study, its conclusions and the review process which should have caught these significant issues. Furthermore, this study should raise the significant ethical concern for the scientific community on the scientific analytical integrity matters.
The conclusions of such a study may impact significantly public policies and have critical consequences for the health of populations exposed to the virus and for whom the vaccine is proposed. The data set should also be publicly communicated for further independent external analysis.
REFERENCES
1. Lundberg-Morris L, Leach S, Xu Y, Martikainen J, Santosa A, Gisslén M, Li H, Nyberg F, Bygdell M. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study. BMJ. 2023 Nov 22;383:e076990. doi: 10.1136/bmj-2023-076990. PMID: 37993131; PMCID: PMC10666099.
2. Yahi N, Chahinian H, Fantini J. Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination. J Infect 83 (2021): 607-635.
3. Liu Y, Yu Y, Zhao Y, He D. Reduction in the infection fatality rate of Omicron variant compared with previous variants in South Africa. Int J Infect Dis. 2022 Jul;120:146-149. doi: 10.1016/j.ijid.2022.04.029. Epub 2022 Apr 21. PMID: 35462038; PMCID: PMC9022446.
4. Shrestha NK, Burke PC, Nowacki AS, Simon JF, Hagen A, Gordon SM. Effectiveness of the Coronavirus Disease 2019 Bivalent Vaccine. Open Forum Infect Dis. 2023 Apr 19;10(6):ofad209. doi: 10.1093/ofid/ofad209. PMID: 37274183; PMCID: PMC10234376.
Competing interests:
No competing interests
28 November 2023
Alexis LACOUT
Medecine
Xavier Azalbert, Alexis Lacout, Jean-François Lesgards, Christian Perronne, Corinne Reverbel, Jean Marc Sabatier, Martin Zizi
Surgical Medical Center of Tronquieres–Elsan, Aurillac, France
Rapid Response:
Concern about Covid-19 vaccine efficiency related to biased analyses not captured by the review process Re: Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study
Dear Editor,
We read with interest the paper by Lisa Lundberg-Morris, et al. (1) which reviewed the Covid-19 vaccine effectiveness against post-covid-19 condition in a population-based cohort in Sweden of 589 722 individuals. It raises a number of significant concerns in the analyses conducted and its conclusions. This paper analyses two cohorts. Cohort A: not vaccinated prior to having Covid-19; cohort B: vaccinated prior to having Covid-19.
The first observation relates to the death ratio in cohort A (0.28%, 821/290030) which is significantly lower (p=0.001) than in cohort B (0.36%, 1076/299692). The risk of death is in fact the most important, while the other items can be qualified as intermediate criteria.
In addition, neutralizing and facilitating antibodies may be produced against the virus. The modeling work published by Yahi et al. shows that antibodies facilitating the spread of the virus (ADE) have more affinity with the spike protein than neutralizing antibodies in regard to the delta variant (on the contrary to what is observed with the original strain of SARS-CoV-2 of 2020, Wuhan/D614G) (2). The appearance of a given variant may thus favour the ADE phenomenon, and could explain why the vaccine (developed from the first strain of the virus) can be deleterious in certain cases. As a matter of fact, 59 349 individuals were excluded from the analysis because events occurred less than 28 days of Covid-19 index date (56 760 vaccinated, 2515 died, 74 emigrated). The reason for exclusion was vaccination for 56 760 patients and death for 2515. The cause of death is unknown and should have been analysed. We do not know how many of these patients were vaccinated. This intermediate group should have been analysed to model the trend or adapt the less than 28 days of covid-19 index date exclusion.
The third observation is related to a cohort bias as cohort A has been exposed to different variants compared to cohort B. 60.2% of persons in cohort A had a variant Alpha predominant during acute infection versus 3.5% in cohort B. And cohort B had variant Omicron predominant at 74.9% vs 12.4% for cohort A.
Populations are heterogenous and cannot be compared as they are not exposed to the same variants, each of which has a different morbidity and lethality. Indeed, Liu Y et al. reported that infection fatality ratio of Omicron variant was reduced by 78.7% (95% confidence interval: 66.9%, 85.0%) with respect to previous variants (3). In Lisa Lundberg-Morris, et al.’s study, the vaccinated population (Cohort B) was predominantly exposed to much more benign variants than the unvaccinated population (Cohort A).
Vaccination effectiveness against post covid-19 condition should thus have been done by variant to cope for the different fatality ratio by variant. This bias, which is of crucial importance, is not mentioned in the limitation of the study.
Last but not least, the risk of infection was higher with the higher number of vaccine doses, which should have been discussed (4). Variant matching is essential to draw a reliable conclusion about vaccine efficacy.
Altogether, we raise serious concerns about the analytical choices made for the study, its conclusions and the review process which should have caught these significant issues. Furthermore, this study should raise the significant ethical concern for the scientific community on the scientific analytical integrity matters.
The conclusions of such a study may impact significantly public policies and have critical consequences for the health of populations exposed to the virus and for whom the vaccine is proposed. The data set should also be publicly communicated for further independent external analysis.
REFERENCES
1. Lundberg-Morris L, Leach S, Xu Y, Martikainen J, Santosa A, Gisslén M, Li H, Nyberg F, Bygdell M. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study. BMJ. 2023 Nov 22;383:e076990. doi: 10.1136/bmj-2023-076990. PMID: 37993131; PMCID: PMC10666099.
2. Yahi N, Chahinian H, Fantini J. Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination. J Infect 83 (2021): 607-635.
3. Liu Y, Yu Y, Zhao Y, He D. Reduction in the infection fatality rate of Omicron variant compared with previous variants in South Africa. Int J Infect Dis. 2022 Jul;120:146-149. doi: 10.1016/j.ijid.2022.04.029. Epub 2022 Apr 21. PMID: 35462038; PMCID: PMC9022446.
4. Shrestha NK, Burke PC, Nowacki AS, Simon JF, Hagen A, Gordon SM. Effectiveness of the Coronavirus Disease 2019 Bivalent Vaccine. Open Forum Infect Dis. 2023 Apr 19;10(6):ofad209. doi: 10.1093/ofid/ofad209. PMID: 37274183; PMCID: PMC10234376.
Competing interests: No competing interests