Emergency authorization was given to be used wisely. Past experiences showed us that clinical trials, safety assessments are here for a reason and in some cases are not sufficient [ ][ ][ ].
This Vaccination is based on limited understaning of short term risks since clinical trials have had short durations for evaluating short term safety (28 days to 4 months), and relatively small samples (12,000 to 25,000 compared to hundreds of millions). Risks of bias are high due to limited studies all done by manufacturers. Lack of critical interpretation of side effects observed during trials, weak pharmacovigilance in most countries in the absence of control groups adds to the problem. In addition to that, many countries stepped out of protocols mainly for logistics reasons or side effects making extrapolations and adding risk to risk.
Clinical trials phase 3 for proper observation were due for most vaccines early 2023. Until, we have sufficient long-term understanding, fully informed consent is medically, scientifically and ethically needed without pressure or temptation of any kind for everyone's benefit.
This is even more true for mRNA vaccines who rely on a novel technology with unknown positive and negative consequences. Efficacy and safety must be reassessed with new trials for vaccine updates and mutations that may alter behavior. Efficacy and safety must be reassessed with trials before use outside of clinical trial protocols that led to emergency authorization or before considering new shots. Efficacy and safety must be reassessed with trials before mixing vaccines or accumulating different versions of vaccines. Safety and efficacy reports and studies from the initial trial must be shared with the population as to continued efficacy and safety.
Observation of efficacy in protecting recipients of vaccines from manufacturers' published studies has its limitations
- It relies on a few hundred people for example the Pfizer study relies on 650 people in total 550 in the control group and 100 on the intervention group for the entire vaccination period and only 171 individuals if we assess efficacy 7 days after second injection. Moderna and Astrazeneca have similar or smaller samples. The results are statistically valid and even strong for the population tested but cannot be extrapolated beyond to show levels of efficacy on subgroups in particular those with comorbidities, combination of comorbidities or for the elderly.
- Efficacy as to severe Covid relies on 10 people for Pfizer.
- There was no covid mortality in either group further indicating that the context was one of either low risk epidemic or low risk sample. It is difficult to establish a reduction of mortality from such a sample particularly for those who need it most that is the elderly, and those with comorbidities.
- In Pfizer's case, there are questions as to 3410 people excluded with « suspected covid » 1594 in the vaccine group and 1816 in the control group which would alter efficacy [ ] In Jansen's case, efficacy seems to be from its recently published study at 66.9% much lower than claimed 90+%. It seems slightly more effective on 60+ on that category. [ ][ ]
- Decision to vaccinate massive populations relies on 1 trial funded and controlled by the manufacturer inducing a bias risk.
- In the case of Pfizer and Moderna, those with history of Covid were excluded making benefit/risk for those already infected impossible to evaluate. Such population is probably large in much of Europe and the US. Most of them may have been already at low risk of severe covid or death and after recovering, their severe covid risk is likely negligible. As they have been explicitly excluded, as their benefit cannot be determined, as their vaccination risk since unknown, must be assumed high, as they are less likely to spread than naive populations and possibly vaccinated, vaccination should be avoided or at least they must be warned.
- Given suspected large numbers of asymptomatic or lightly symptomatic populations whom may not know they had covid, they must at least be offered cellular reactivity tests before making a free informed decision.
- Efficacy relies on small numbers, is demonstrated for populations with limited benefit from vaccination and unknown thus high long-term risks. It is less clear for those at high risk and is not demonstrated on mortality.
Observation of short-term safety also calls some questioning
- In Pfizer's case, there are 371 individuals who have been excluded from the statistical analysis on or prior to 7 days after second injection. No reports have been given about disease course for these individuals. Instead of excluding them, this would have given insight as to ADE risks and risks before vaccine effect is fully active
- The imbalance in these 371 excluded individuals 311 in the vaccine group and 60 in the placebo group calls for further questioning. This questionning becomes all more pressing as reports seem to indicate that such unexplained imbalance with higher levels of infections immediately after vaccination. This imbalance should have been investigated to ensure absence of an increased susceptibility risk after vaccination.
- Excluded populations such as those with history of covid, immunocompromised, those with immunosuppressive therapies leaves us without clinical trial to validate responsibly benefit/risk
- There is no data as to risks to if and when immunity starts to weaken in presence or absence of virus encounter
- Significant adverse effects (fever in 16% of the young) comparable to those of the disease itself in younger healthy individuals have been observed. Yet outcome of those excluded must be made public before conclusions for Pfizer. Israel mortality analysis including that of age 15-44 needs to be made public to understand better. Jansen's safety analysis relies on a relatively small sample 3356 individuals.
Observation on long term safety
- mRNA vaccines are a new technology-, mid- and long-term side effects are unknown.
- Precautionary principle and responsibility calls for assuming that such risk maybe significant
- Other non mRNA vaccines do not yet have enough observation time and their risks are unknown
- Better midterm understanding would be available early 2023 when comparing conditions of the intervention group with the control group if we are to have a scientific protective approach
- Phase 3 raw data, if released progressively may give more insight
- Phase 4 should adapt to compensate for this quasi experimentation by having active monitoring of all vaccinated individuals and releasing such data
- For consistency data related to hospitalizations and mortality within 45 days after vaccination should be reported to identify those dead with vaccine just like we identified those dead with covid and monitor for any unusual numbers
A preliminary study from Denmark suggests some efficacy 64% in infection reduction 7 days after Pfizer second dose for Care Home Residents and very limited protection before. This is promising if it translates into severe course and mortality reduction as it would indicate that one of the niches who need vaccination and are at relatively low risk of long-term side effects would get benefit.[ ] Such niche or benefit could be confirmed after above mentioned all causes mortality have been fully investigated and explained. It would validate vaccination for a large portion of those at risk.
In addition to previously stated limitations related to sampling, partial unblinding, exclusions[ ],,exclusion criteria, efficacy by group, Efficacy demonstrated for those with least benefits and highest risk of side effects, short term perspective... Analysis for several vaccines including Pfizer and Moderna was done exclusively on Relative Risk Reduction and did not include Absolute Risk Reduction and Numbers Needed to Treat.[ ] This is a way to present information on its best facet but all these criteria are needed when it is time to make a decision.
For example, in the Pfizer study, if we look at severe disease outcome. There were 9 cases in Placebo group out of 21728 and 1 in the vaccine group out of 21720. That is respectively 0,041 % and 0,005 %. That tells that over study period vaccination has reduced risk of severe Covid from 0.041 % to 0.005 %= risk reduction of 0.36 %. It also tells that to reduce 1 case of severe Covid one needs to vaccinate 2715 individuals who will be at risk of short- and long-term side effects if massive vaccination is performed.
On the other hand, for Pfizer trial, there were 4484 related adverse side effects in the vaccine group and 1095 for placebo. This means a Relative Increased Risk (RIR) of 61 % and an Absolute Increased Risk (AIR) of 15 % which is high particularly that adverse events are more common in the younger population who most often have a mild course of disease. Severe adverse events were in 240 in the vaccine group and 139 in Placebo group equivalent to an RIR of 27 % and an AIR of 0.46 %. This means to avoid 1 severe Covid case 733 will suffer from side effects and 13 would suffer from severe side effects.
This calls for targeted vaccination towards those with benefit and low risk of such adverse events. The young and healthy are also those at highest risk of long-term side effects of this novel technology. It goes without saying that those recovered cannot be vaccinated outside of a new clinical trial as they were excluded from the trial, their benefit unknown likely low and risks unknown thus should be assumed high.
Looking at the NNT for Moderna to prevent severe covid, 30 placebo group members had severe Covid and 185 had covid in the placebo group and 11 in the vaccine group. This corresponds in the context of the trial described by the authors as an environment of « appreciable risk », to vaccinating 15210 individuals. In that context NNT is around 507 (15210/(30-0)) to prevent severe Covid and around 87 to prevent mild or moderate Covid 19 (15210/(185-11)) . The rough result would mean on the short-term vaccinating 15210 individuals results in sparing 173 mild or moderate symptoms, 30 Hospitalization on the one side.
On the other hand grade 3+ events occurred in 15.8 % that would mean in trial context 2403 individuals had a serious non-life threatening adverse event that may require hospitalization. Adverse events were more common in the younger whom had least benefit from vaccine protection.[ ][ ] It also means that in context of clinical trial, to avoid 1 case of serious Covid 19, 80 individuals would suffer from grade 3 adverse side effect. This is high and again as the young get least benefit and are at highest risk of such adverse events, it calls for targeted vaccination towards those with benefit and low risk of such adverse events. There have also been imbalances in some severe side effects which should have been explored in greater details before proceeding to recommend intervention massively. The young and healthy are those at highest risk for long term side effects of this novel technology. It goes without saying that those recovered cannot be vaccinated outside of a new clinical trial as they were excluded from the trial, their benefit unknown likely low and risks unknown thus should be assumed high.
Janssen’s vaccine had been approved in Europe and the USA many months before any studies were published . Press releases were marketing it as a product promising 85 % efficacy, authorities in Europe and the US gave an emergency authorization for this vaccine and never contested such publicity outside of any scientific publication or even pre-print. As the publication came out a few months later, it turns out efficacy as per the study of the manufacturer is 66.9 % in preventing Covid 19 that is 18 % lower. However, it seems to have as good or better RRR for older population who need it most. For Severe Covid there were 19 individuals in the vaccine group and 80 in the placebo group indicating an efficacy of around 80 % on what is ultimately a small sample. The vaccine group was 19630 and placebo group was 19 691. That would give us for an absolute risk for severe Covid of in the context of the trial of 0.09 % for the vaccine group and of 0.4 % for the placebo group corresponding to an ARR of 0.31 %. It would also mean that to avoid one severe covid the NNT value would be around 323.
Janssen’s study reports sufficient sample sizes for obesity, hypertensions and type 2 diabetes. Thromboembolic events occurred in 11 cases in the vaccine group and 3 in the placebo group corresponding to a Relative Increased Risk of 78 % and an Absolute Increased Risk (AIR) of 0.04 % which remains high and should have triggered more attention and more exploration particularly that one such case was grade 4. RIR of 80 % and AIR of 0,016 % of was observed for Seizures. 6 cases of Tinitus, 1 cerebral hemorrhage and 1 case of the Guillain–Barré were observed. AIR of systemic event would be 1.7 % in the young and 0.4 % in those above 60. In context of this trial, for 1 severe case avoided, 5 would have a systemic reaction and 0.33 would have a serious side effect. This is a high number, strongly urging for targeted vaccination towards those with a clear identified benefit particularly that long term side effects remain unknown and efficacy towards new variants remains unknown. However, late publication, arrival of such publication after suspension in the US because of thromboembolic events occurring in real population, disclosure of such known risk and others by the study after-market authorization, inconsistencies between the text of the NEJM study and tables S6-S9 of the appendices, all call for caution. This preliminary analysis relies on the text of the NEJM study rather than the appendices.
This only accounts for the short-term risks and further urges towards vaccinating those have a significant possible benefit. Those with limited benefit are at higher risk of short-term adverse events and long-term ones as we have no knowledge of long-term efficacy or side effects. If needed be, this further stresses importance of targeted vaccination towards those at risk to avoid unwarranted serious side effects and long term consequences on those with low risk in addition to wasting vaccine doses and preventing others whom may have a benefit from gaining access in less developed countries.
There are exclusions whose outcome has not been published, high rates of significant or severe side effects identified by studies particularly in young healthy individuals, there are even inconsistencies in the case of Janssen between the study and its appendices.
We request that the raw data be made public so that at least data can be analyzed short term, and that ongoing collected data comparing vaccine group and placebo continue be made public as follow up data for safety.
Economic analysis also favors that course. Above example for Pfizer implies several costs, Vaccinating 2715 individuals to prevent 1 serious disease comes with a cost of around $95 000 paid to the manufacturer to which must be added:
- cost of vaccination act.
- cost of treatments and possibly hospitalizations of grade 3 adverse events caused by vaccines.
- cost of work stopping.
From which must be deducted:
- cost of treatment of that 1 serious case and that of mild cases.
Targeted wise vaccination would be beneficial for health of vaccinated population, their economy and solidarity between nations.
Multiple reports indicate that vaccinated individuals can still be infected in large proportions, can also be infectious and including turn out to be super spreaders.
As variants are emerging concomitantly with vaccination campaigns using different vaccines, special caution must be taken towards pressure selection further leading to mutations that escape vaccinal immunity. This risk is highest as many vaccines, particularly the ones above mentioned target only the spike protein. Efficacy of vaccines must be determined against circulating variants from real life data as preliminary reports indicate significant reduced efficacy on some variants at least for Pfizer.[ ]
Targeted vaccination is needed as new mutations are happening and current vaccines may become obsolete fast, vaccination accumulation comes with risks benefits that will need to be assessed. We cannot just target an accumulation of failures and add risk to risk into unchartered territories.
Targetted vaccination is warranted as large portions of population in many countries are already immunized naturally against the full virus and may better resist mutations. Their benefit from vaccination is minimal if any and their risks depend on vaccines. For that matter, Pfizer and Moderna assumed past infection as being an exclusion criteria.
Efficacy, cost and safety would be completely different in case of a targeted vaccination towards those at risk provided efficacy and safety are demonstrated. From a public health perspective RRR, ARR and NNT can lead to very different decisions as to sampling and choosing. A community may be mislead and vaccinate excessively the wrong population with avoidable side effects and long-term consequences.
Many theoretical risks may be feared particularly from mRNA vaccines. We don’t know if multiple vaccinations may lead to unforeseen outcomes nor do we know bodies’ reaction after meeting a mutant or another coronavirus. The truth is we don’t know enough and should not add risks to risks. We do not know efficacy agaisnt some emerging strains.
An emergency authorization was granted to Jansen's vaccine in the US and Europe before publication of clinical trial results. Its use has been suspended since then in the US further indicating that we are in unchartered territories independently of future analysis. Astrazeneca vaccine was also suspended in several countries after harm was suspected on young healthy individuals who were at low risk of severe covid or covid death. Some of them may have been at negligible risk, had they recovered already from Covid or had they developed cellular immunity with light symptoms.
It has been suggested that manufacturers would adapt their vaccines to new variants. Each adaptation would require a clinical trial and special safety tests associated to vaccine accumulation covering similar targets in a short time span.
It has been suggested to skip all protocols and give some people a third injection or even mix vaccines outside of any trials.
An additional concern arises from Pfizer's and possibly other manufacturers' proposal to vaccinate control groups thus making it harder to identify imbalances and possible long term side effects. This additional step away from evidence based science combined with requests to limit manufacturers' liablities is most worrying.
The absence of carcinogenicity studies also raises questions, as the injected components are lipidic but lead to the production of an unusual free protein whose long-term effects are unknown. The question of cancers can therefore be raised.
There is potential to mRNA vaccines but it needs to be tested thoroughly as we always did.
Hypotheses need to be tested as often they turn out to be false.
As indicated in previous section, from mortality data, the data of the big picture paints an image of failure of one size fits all massive vaccination in spite of media trying to present things otherwise and social media trying to control the debate.
There seem to be an imbalance in the analysis of above mentioned studies exploring in length benefits to the detriment of a short less extensive analysis of side effects, their consequences and by definition long term side effects. Post vaccination vigilance is weak in most countries and little is done for comparisons with control groups.
The evidence for healthy individuals is probably moderate to strong. The benefit for these individuals is weak as they are at low risk of covid mortality. The risk of side effects is high based on known side effects but also given that we have no knowledge of long term impacts particularly for mRNA vaccines.
The evidence for the elderly whom have not had covid was weak to moderate and has improved slightly with above mentioned Danish study. The risk of long-term side effects is to be assessed based on their life expectancy. Ultimately, it should be their decision without pressure or temptation.
Evidence for vaccinating the elderly was not provided by the study but rather by data collected by real life use on populations. We should be careful with experimentations as data could go one way or another. The elderly were included in the Pfizer trial even if in insufficient numbers. Efficacy was not demonstrated but they could have hoped for a benefit. Maybe they did and maybe we will be reassured after excess mortality in above mentioned countries is fully explained.
The evidence for those who have recovered from Covid is absent. Their benefits are negligible [ ][ ] and risks are high. It must also be taken into account, current knowledge as to long lasting memory immunity protective effect [ ][ ]. Looking merely at antibodies is insufficient as cellular immunity plays a major role possibly more significant than that of antibodies.
The evidence for those under immunosuppressive treatment and those immunocompromised is unknown.
No one can responsibly make a claim as to the long term safety of these new vaccines.Vaccines have a niche, people should be fully informed without pressure or temptation but current marketing to magnify advantages and minimize risks is not compatible with science or medicine nor does it benefit humanity.
A nuanced approach is needed. Tables 1, 2, 3, 4 provide a risk benefit analysis for 3 vaccines, and different vaccination approaches.