In most western countries, the mass Coronavirus disease-19 (COVID-19) vaccination campaigns which have been ongoing since the end of 2020 are based on two mRNA vaccines against SARS-CoV-2 (BioNTech/Pfizer BNT162b21 and Moderna mRNA-12732). Both products received Emergency Use Authorization (EUA from the FDA in the USA) and Conditional Marketing Authorization (CMA from EMA in EU), based on the results of clinical trials which have raised a lot of controversy (here and here)3,4. In particular, product safety in those trials was evaluated only through adverse event (AE) reporting by the participants, and no clinical laboratory assessment was considered except in the small phase I part of the trial program, where just a few dozen participants were enrolled. However even such a small sample was enough to identify several laboratory changes: for example, the BioNTech/Pfizer phase I study recorded between 8.3% and 33.3% grade 3 decreases in the lymphocyte count in each dose group and grade 2 neutropenia in two other participants5. Despite such findings, no clinical laboratory evaluations were subsequently included in the phase III trial6.
According to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, clinical laboratory evaluations are a key part of the overall safety evaluation of any new drug. In particular, according to the Common Technical Document (CTD) Efficacy (M4E)7, which describes the structure and format of the clinical data in a new drug application, a specific section (2.7.4.3, a subheading of section 2.7.4 Summary of Clinical Safety) should describe changes in patterns of laboratory tests with drug use, with appropriate comparisons of the treatment and control groups. Laboratory data should include “haematology, clinical chemistry, urinalysis and other data as appropriate”, and “each parameter at each time over the course of the study (e.g., at each visit) should be described”.
The same CTD clearly recommends to consider “laboratory findings reflecting actual or possible serious medical effects“, since “examination of which subjects experience extreme laboratory value abnormalities ("outliers") may be useful in identifying subgroups of individuals who are at particular risk for certain adverse events” (section 2.7.4.2.1 Analysis of Adverse Events).
The ICH guidelines pertaining to the CTD Efficacy (M4E) have been fully implemented by all ICH Members, and in particular by FDA (USA) and EMA (EC, Europe)8. Unfortunately, no regulatory agency has considered asking for the results of laboratory tests in COVID-19 vaccines phase III studies, consequently losing the opportunity to collect information about tissues, organs and functions more prone to adversely react to vaccines. Remarkably, on the contrary in COVID-19 a lot of effort has been dedicated to the identification of conventional and novel laboratory tests and biomarkers to assess for example the risk of thrombosis and prognosis, to aid risk stratification, and potentially even to guide therapy9. A similar approach with COVID-19 vaccines could contribute to the timely identification and effective treatment of AE following vaccinations, and consequently to increase confidence in the safety of vaccines and to reduce vaccine hesitancy.
Indeed, few but nonetheless convincing studies exist indicating that laboratory tests after vaccination may help to better characterize vaccine-induced effects, eventually leading the identification of subjects potentially at risk for the development of clinically relevant adverse reactions. For example, a small study in 281 subjects, 138 vaccinated with ChAdOx1 nCoV-19 (AstraZeneca) and 143with BNT162b2 (BioNTech/Pfizer), showed that 19 (6.8%) tested positive for anti-PF4/polyanion antibodies postvaccination (5.6% of those who received BNT162b2, and 8.0% of those who received ChAdOx1 nCoV-19)10. Anti-PF4/polyanion antibodies have been associated with vaccine-induced immune thrombotic thrombocytopenia (VITT). In this study, antibody levels were fortunately never high enough to induce platelet aggregation, however subjects with anti-PF4/polyanion antibodies might well be considered a subgroup at risk for VITT, and consequently being offered long term monitoring and eventually a timely treatment would clinical progression occur in selected cases.
Likewise, a recent study looking for cardiovascular effects in 301 students, aged 13–18 years and who received the second dose of the BNT162b2 COVID-19 vaccine, found 7 participants (2,3%) exhibited at least one elevated cardiac biomarker or positive lab assessments, 1 participant with myopericarditis, 2 participants with suspected pericarditis and 4 participants with suspected subclinical myocarditis11. As a whole, cardiovascular effects were found in 29.2% of subjects, ranging from tachycardia, palpitation, and myopericarditis, and laboratory assessment of cardiac biomarkers provided a major contribution to the effective monitoring of this specific population.
A third study deserving consideration was performed in 50 patients who experienced post-acute sequelae of COVID-19 (PASC)-like symptoms following SARS-CoV-2 vaccines, in comparison to 10 healthy subjects and 35 vaccinated subjects without PASC-like symptoms12. Markers of platelet activation and increased pro-inflammatory cytokines were found in blood of vaccinated subjects with PASC-like symptoms together with circulating monocytes which expressed vaccine-induced SARS-CoV-2 spike protein, possibly representing a biomarker signature for at least some kind of AE following COVID-19 vaccination.
Finally, it is worth mentioning a study that has so far only been presented at a congress and whose summary, which appeared in a prestigious international journal of clinics and therapeutics of cardiovascular diseases, aroused many discussions at the time13. The study considered 566 patients followed in a cardiology clinic for cardiovascular risk assessment and documented an increase in various inflammatory markers known to predict the 5-year risk of acute coronary syndromes following BioNTech/Pfizer or Moderna mRNA vaccines.
To our best knowledge, only these relatively small studies so far addressed by means of clinical laboratory assessment a few specific issues related to post-vaccination AE, namely thrombotic thrombocytopenia and myopericarditis, which represent the two main groups of adverse reactions so far related to COVID-19 vaccines. Regrettably, no similar studies exist so far in different post-vaccination AE, such as acute myocardial infarction, Bell’s palsy, cerebral venous sinus thrombosis, Guillain–Barré syndrome, stroke, other neurological complications, pulmonary embolism, lymphadenopathy, appendicitis, herpes zoster reactivation, autoimmune conditions (e.g., autoimmune thyroiditis or hepatitis, peripheral neuropathies, etc.), or other less well defined disturbances reported after COVD-19 vaccines, such as dysautonomic syndromes, paraesthesias, painful syndromes and many others. Anyway, the study in vaccinated subjects with PASC-like symptoms has particular merit since, wherever confirmed and reproduced, it could provide a peculiar pattern of biomarkers of great value to better characterize and substantiate many heterogeneous and often ill-defined conditions, which may occur following COVID-19 vaccination. The same could be said of the study on acute coronary syndrome risk markers.
The fact that COVID-19 vaccines were authorized with no information about any possible relationship between AE following vaccines and pre- or post-vaccination laboratory findings, led governments and institutions to not recommend (and in some cases even to recommend not) to perform any kind of examinations before or after vaccinations, in the well-known misunderstanding that “absence of evidence is evidence of absence”. In Italy, many advised against clinical laboratory tests before or after vaccinations, for example the national federation of orders of surgeons and dentists (FNOMCeO)14.
In conclusion, there is an urgent need to assess any patterns of clinical laboratory findings occurring in subjects before and following vaccination, as it could be of major help:
- in the assessment, prediction and prevention of individual risk, allowing the identification of subgroups of individuals who are at particular risk for AE as well as the better understanding of the pathophysiological mechanisms underlying specific AE;
- in the evaluation of suspect AE following vaccination, contributing to the definition of any eventual relationship between AE and the vaccines and encouraging the spontaneous reporting of the AE to the pharmacovigilance systems;
- in general, in reassuring the public about the safety assessment process of these COVID-19 vaccines, consequently leading to a more safe and effective use of these vaccines and to the overcoming of vaccine hesitancy.
Routine clinical laboratory and instrumental testing should be offered to anyone willing to receive the vaccine as part of the clinical assessment in selected vaccination hubs. Assessment should be performed before vaccination and regularly thereafter, at regular intervals. This would make it possible to collect priceless information in a short time and with very limited costs and difficulties.
European Medicines Agency. Comirnaty Assessment Report. 2020. EMA/707383/2020. Available online: https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf (last accessed: 20th august 2022).
European Medicines Agency. COVID-19 Vaccine Moderna Assessment Report. 2021. EMA/15689/2021. Available online: https://www.ema.europa.eu/en/documents/assessment-report/covid-19-vaccine-moderna-epar-public-assessment-report_en.pdf (last accessed: 20th august 2022).
Doshi P, Godlee F, Abbasi K. Covid-19 vaccines and treatments: we must have raw data, now. BMJ 2022;376:o102.
Doshi P. Peter Doshi: Pfizer and Moderna’s “95% effective” vaccines—we need more details and the raw data. URL: https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-modernas-95-effective-vaccines-we-need-more-details-and-the-raw-data/ (last accessed: 20th august 2022).
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https://www.ich.org/page/ich-guideline-implementation (last accessed: 20th august 2022).
Gorog DA, Storey RF, Gurbel PA, Tantry US, Berger JS, Chan MY, Duerschmied D, Smyth SS, Parker WAE, Ajjan RA, Vilahur G, Badimon L, Berg JMT, Cate HT, Peyvandi F, Wang TT, Becker RC. Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium. Nat Rev Cardiol 2022;19:475-495.
Thiele T, Ulm L, Holtfreter S, Schönborn L, Kuhn SO, Scheer C, Warkentin TE, Bröker BM, Becker K, Aurich K, Selleng K, Hübner NO, Greinacher A. Frequency of positive anti-PF4/polyanion antibody tests after COVID-19 vaccination with ChAdOx1 nCoV-19 and BNT162b2. Blood 2021;138:299-303.
Mansanguan S, Charunwatthana P, Piyaphanee W, Dechkhajorn W, Poolcharoen A, Mansanguan C. Cardiovascular Manifestation of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents. Trop Med Infect Dis 2022;7:196.
Patterson BK, Francisco EB, Yogendra R, Long E, , Pise A, Beatyn C, Osgood E, Bream J, Kreimer M, Vander Heide R, Guevara-Coto J, Mora R, Mora J. SARS-CoV-2 S1 Protein Persistence in SARS-CoV-2 Negative Post-Vaccination Individuals with Long COVID/ PASC-Like Symptoms, 12 July 2022, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1844677/v1]
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Clinical laboratory evaluation of COVID-19 vaccines in clinical trials
Doctor Cosentino thank you for having put together such an exhaustive summary of what would be needed in order to properly track adverse events related to COVID vaccines. I hope to share your article with my English- speaking friends and colleagues because thus far I've only been able to share Italian articles. Furthermore I'm really glad to see you are using substack, which is quickly becoming a valid alternative to national and international media outlets, most of which have not been doing their jobs. It seems we are suffering from an ethical degradation of norms that we had taken perhaps for granted. This applies to medicine as much as journalism.
isn't criminal the behavior of FNOMCeO?
how is possible that they don't only don't do their work but actively avoid others to do it? but I guess I have to ask a lawyer, anyway really shocking (with rest of the article) didn't know that, doing only show what the situation is, the word corruption isn't even enough anymore to define this it seems...