Pandemic Journal Dr Robert Hess Archive

Dr Robert Hess: How do viruses interfere with the p53 pathway?

Dr Robert Hess – 12/06/2021

Dr Robert Hess: How do viruses – and more particularly SARS-CoV-2 – interfere with the p53 pathway?

We look at the strategies employed by viruses against this tumor suppressor gene.

Since the onset of the pandemic, research has been conducted into the extent to which SARS-Cov-2 affects the p53 tumor suppressor gene and its pathway. Two widely published studies from 2020 and 2021 have provided interesting insights into this, revealing the molecular strategies by means of which viruses such as SARS-CoV-2 target the p53 function. It is also interesting to compare the combat strategies of other viruses with those of SARS-CoV-2, and we will also briefly discuss this below.

Virtually all viruses have evolved strategies and molecular tools to disable and/or control cell regulatory mechanisms in their hosts that might otherwise impede replication, dissemination or persistence. To this end, viruses have evolved specific proteins to target cell decision centers that regulate cell proliferation and survival as well as the innate immune response mechanisms used by cells to defend against viral infections, for example interferon-gamma-mediated antiviral responses.

Among these decision centers and mechanisms, the p53 tumor suppressor protein plays an important role. This stress-inducible factor can directly and indirectly command a variety of signaling pathways that control DNA replication and repair, cell proliferation, programmed cell death, metabolism and innate immune responses. This broad spectrum of suppressive effects makes p53 a highly “legitimate” target for many different cancers which seek to inactivate it by mutation, deletion or other mechanisms.

The p53 protein was originally discovered as a cellular target of the large T antigen (LT) of the oncogenic Simian Virus 40 (SV40). Over the years, a number of studies have identified an astonishing variety of molecular devices employed by each known viral family to hijack, control or impair the functionality of p53. In persistent oncogenic viruses, such as the human high-risk papillomaviruses (HPV 16, 18, 31, 45), these devices are so specific and powerful that they permanently inactivate p53 functionality and produce an oncogenic effect. Non-oncogenic viruses also produce proteins that interact with p53 or p53 regulators, thereby confirming that control of p53 is an essential mechanism to support efficient viral replication, propagation and in some cases persistence.

In this article, we briefly summarize the current state of knowledge regarding the mechanisms by which viruses interfere with the p53 pathway and the consequences that flow from this. We then discuss the evidence to date on how SARS-CoV-2 attacks the p53 pathway and look at the potential functional impact of this disruption on replication, pathogenesis and the potential long-term consequences of infection.

VIRAL STRATEGIES FOR THE CIRCUMVENTION OF P53
Seen from the perspective of a virus, the presence of an active p53 in the host cell represents a threat that must be neutralized or circumvented in order for the virus to go about its business of replication and propagation. The most immediate challenges posed by p53 are stress-induced programmed death of the host cell and induction of innate or adaptive immune responses of the antiviral kind. Programmed cell death – primarily through apoptosis – is a radical protective response at cellular level that effectively destroys the viral host cell. The p53 protein acts as a stress-activated switch for many pro-apoptotic pathways, so by seizing command of this switch, the virus ensures that it can control the survival and lifespan of its host cell.

The mechanisms chosen by individual viruses to the detriment of p53 depend on cell tropism, propagation cycle, and modalities of latency or persistence. In the next section, we give examples of three strategies that viruses use to target the p53 pathway: Hit and Run, Hide and Seek, Kidnap and Exploit. The name given to each of these strategies describes how the virus exploits the host cell for its own replication and propagation purposes and reveals the perfect adaptation of the virus to a particular ecological niche.

Hit and Run
Exemplifying the Hit and Run strategy is the influenza virus (IAV), a member of the Orthomyxoviridae family of RNA viruses and one of the most common agents of human respiratory infections. Speed is of the essence for IAV, as the time available to it for the cycle of infection, replication, and reproduction is very short. This cytolytic virus triggers host cell apoptosis to promote the release of virions from infected cells. It therefore employs the unusual strategy of attacking p53 to activate its ability to trigger programmed cell death.

Hide and Seek
This viral strategy comprises two sequential phases: first, the attenuation of p53 functions (hide) and second, the positive mobilization of p53 (seek) to support the virus at different stages of its life cycle. A typical example of such a hide-and-seek strategy is HIV-1, a lentivirus that latently infects CD4 lymphocytes and causes a loss of T-helper functions that in turn leads to AIDS. HIV-1 has evolved several proteins that target p53 either early or late in the viral life cycle.

Kidnap and Exploit
This strategy is a somewhat more sophisticated form of Hide and Seek in which the virus manipulates p53 with a whole range of molecular tools, not only to attenuate the antiviral effects mediated by p53, but also to exploit p53 as a factor that controls and facilitates viral replication. Examples of this strategy include members of the Herpesviridae family, such as herpes simplex virus 1 (HSV-1) and Epstein-Barr virus (EBV). Infection with HSV-1 is often asymptomatic: it manifests itself mainly as benign herpetic skin and mucosal lesions, but due to its persistence in neurons, the virus can also cause latent, recurrent infections.

HOW DO SARS-COV VIRUSES INTERFERE WITH THE p53 PATHWAY?
Information on how SARS-CoV-2 targets and manipulates the p53 pathway is still sparse and limited. However, the information we have for SARS-CoV-1 is more detailed. Given that the two viruses are approximately 89% genomically homologous and share many similarities in their infection and pathogenesis mechanisms, it is reasonable to speculate that both viruses use similar molecular mechanisms to target and circumvent p53.

The observations summarized above underscore the fact that SARS-CoV viruses, like most other virus families, have evolved and developed molecular tools that are well adapted to targeting p53 and its signaling pathway. The strategy followed by these viruses shares similarities with the kidnap-and-exploit strategy described above for EBV and HSV1. The distinguishing feature of this strategy is the hijacking of p53 by viral antigens that initiate alternative pathways for the degradation of p53, thereby not only impairing the suppressor functions of p53 but also protecting it from regulation under stress conditions. This mechanism shifts p53 from its normal cell response pathway to a viral response pathway, allowing the virus to bypass components of the p53-controlled pathways or even use them to its own advantage. How this mechanism affects the pathogenesis of SARS-CoV infections and, in particular, the progression of Covid-19 remains a matter for conjecture for now. Two scenarios can be considered:

1) p53 could serve as an antiviral factor that limits SARS-CoV virus replication and reproduction. Consequently, the rate and extent of virus replication might depend on how efficient it is in causing p53 degradation.

2) In parallel with the impairment of p53, SARS-CoV viruses also set in motion molecular programs that lead to oxidative cell and DNA damage and have the potential to hyperactivate p53, resulting in rapid and massive apoptosis. This mechanism could be a contributory factor in the severe lung inflammation and respiratory distress seen in severe forms of Covid-19. Again, p53 could act as a regulator, with the extent of cell and tissue damage depending on the intensity of the p53-mediated responses.

Placing these two scenarios in sequence, one can speculate that SARS-CoV tools (e.g. nsp3 or RCHY1) rapidly switch off p53 function upon infection, thus protecting the virus from innate immune responses and allowing replication. As replication and virus production begin to decline, p53 again becomes available for activation by DNA damage and other stress response pathways of the cell. At this point, the host cell has accumulated considerable oxidative damage, causing p53 to enter a hyperactive state. This, in turn, may contribute to setting in motion a sequence of events that leads to severe inflammation and tissue damage.

Further investigation is needed to determine whether restoring and normalizing p53 activity could be an accessible and affordable objective for Covid-19 therapy. To us, this seems to be a promising target, and we endorse the focus on p53 and its pathway. Further studies are already underway, and we continue to stay on top of the latest developments. The methylation of p53 genes is already central to the epigenetic monitoring of our Premium clients, with review and analysis taking place every three months. The current direction taken by pandemic with regard to SARS-CoV-2 and its impact on p53 further increases the need for monitoring. My traditional focus is on cancer prevention, and since the beginning of the pandemic, we have also become deeply involved in immunology. We are therefore following the fusion of these two areas of research with great interest.

Dr Robert Hess: Heavily mutated Covid variant has been identified.

Dr Robert Hess – 11/28/2021

Dr Robert Hess: Heavily mutated Covid variant has been identified, rapidly labelled a “variant of concern” and named Omicron.

Infection Omicron was first detected in South Africa last week, leading countries around the globe, including the United States, to impose travel restrictions on the southern African nation and at least seven others in the region. The new Omicron coronavirus variant kept spreading around the world on Sunday, with 13 cases found in the Netherlands and two each in Denmark and Australia, even as more countries tried to seal themselves off by imposing travel restrictions. The variant has now been detected in Britain, Germany, Italy, the Netherlands, Denmark, Belgium, Botswana, Israel, Australia and Hong Kong.

Omicron was first detected in South Africa last week, leading countries around the globe, including the United States, to impose travel restrictions on the southern African nation and at least seven others in the region. The new Omicron coronavirus variant kept spreading around the world on Sunday, with 13 cases found in the Netherlands and two each in Denmark and Australia, even as more countries tried to seal themselves off by imposing travel restrictions. The variant has now been detected in Britain, Germany, Italy, the Netherlands, Denmark, Belgium, Botswana, Israel, Australia and Hong Kong.

The discovery of Omicron, dubbed a “variant of concern” last week by the World Health Organization, has sparked worries around the world that it could resist vaccinations and prolong the nearly two-year COVID-19 pandemic. Omicron is potentially more contagious than previous variants, although experts do not know yet if it will cause more or less severe COVID-19 compared to other strains.

There have been many examples of variants that have seemed scary on paper, but came to nothing. The Beta variant was at the top of people’s concerns at the beginning of the year because it was the best at escaping the immune system. But in the end it was the faster-spreading Delta that took over the world. Beta was all immune escape and nothing else, Delta had infectivity and modest immune escape – Omicron potentially has both to high degrees.

What is this variant?
There are thousands of different types, or variants, of Covid circulating across the world. That’s to be expected because viruses mutate all the time. But this new variant, called B.1.1.529 or Omicron, has experts particularly worried because it is very different to the original Covid, which current vaccines were designed to fight. It has a long list of genetic changes – 50 in all. Of these, 32 are in the spike protein of the virus – the part which is the target of vaccines.

It is a rapidly evolving situation and we will keep you up to date with important findings. Omicron’s genetic profile has raised concerns, but there’s a shortage of real-world data that means nobody has the complete picture of what it can do.

Several vaccine manufacturers have announced measures against the new variant Omicron:
BioNTech and Pfizer are testing in the lab until about Dec. 10 how well their own already-approved vaccine protects against Omicron. If necessary, they will develop a vaccine adapted to the variant. Moderna is testing how well its licensed and the new variant-adapted vaccine candidates under development protect against Omicron. It is also directly initiating development of a vaccine adapted to Omicron. AstraZeneca is also evaluating how well its licensed vaccine protects against Omicron, according to the media report, and believes it can quickly develop an adapted vaccine if necessary. Janssen is also evaluating whether its own vaccine is protective, according to the media report. Novavax has started developing a variant of its own vaccine adapted to Omicron, according to the media report.

For now, this is just an update on the current situation and an initial assessment. In the course of the week, we will gain further insights and go into more detail on this topic. We will put current booster recommendations for our customers to the test again. Depending on how the situation develops, we may deviate from the original plan in some cases.

Dr Robert Hess: Update on Booster jabs and vaccine breakthroughs.

Dr Robert Hess – 11/26/2021

Dr Robert Hess: Update on Booster jabs and vaccine breakthroughs.

Infection rates in Germany, Austria and the Netherlands have risen to a new and worrying high. Hospitals have had to postpone planned surgical procedures, and intensive care units are rapidly filling up. The situation in Germany is unfortunately a forerunner of what is likely to happen in the United States soon. The UK had the unwelcome distinction of being ahead of the curve in Western Europe, although the rate there now seems to be leveling off. We expect the current fourth wave will hit the USA in a few weeks. There are two main reasons for this: firstly, waning vaccine efficacy paired with vaccine breakthroughs, and secondly, the slow progress being made by the booster vaccination campaign. More and more studies are showing what we already concluded a few weeks ago, namely that the protection afforded by the vaccines is declining at a rapid rate and that antibody counts are also falling fast.

Eleven months ago, there was great jubilation at the test results from a study conducted by BioNTech which showed that their vaccine had a 95% success rate against infection with the SARS-CoV-2 virus. Not long after, Moderna reported a similar impressive result. This was all the more encouraging, because the FDA had set a modest efficacy threshold of only 50%. Since then, billions of people have been vaccinated against the coronavirus, and numerous studies have confirmed the high protective effect in practice.

Unfortunately, it is now clear that even a double dose of vaccine is not going to be enough to end the pandemic. There were indications of this relatively early on when the initially high antibody titers in the blood of vaccinated individuals dropped again just a few months after they had received their second dose. In Israel, which had vaccinated its population earlier and faster than any other country, the infection curve rose steeply again in the summer, but this has since been flattened out and brought under control by the booster vaccination roll-out.

In Germany, too, it is primarily unvaccinated Covid-19 patients who are occupying beds in intensive care units, but the number of breakthrough infections is also rising. This does not come as a complete surprise from an immunological perspective, as we know that vaccine protection gradually wears off after approximately six months.

Large-scale analyses from different countries now reveal the extent to which vaccine protection declines over time. Scientists in Israel recently published the results from their analysis of cases involving vaccinated adults who had contracted Covid-19 between 11th and 30th July. These showed that individuals who had been vaccinated seven months earlier were at twice the risk of infection as those who had been vaccinated only five months earlier. A study by Pfizer also reached the same conclusion.

An analysis from Sweden produced an even more unpleasant surprise. The research team there found that protection against infection was no longer detectable at all seven months after vaccination and that even protection against hospitalization was down to only 42 percent. Another study from the UK made a comparison using the case-control method. According to this observational study, protection against infection two months after vaccination was 96 percent compared to the placebo group. Five to seven months later, however, it had dropped to 84 percent. Data from the USA also show the diminishing effect.

The effectiveness fades particularly quickly in the elderly, whose immune system responds more weakly anyway. And people in this most at-risk group are precisely the ones whose protection depends on vaccination administered more than six months previously.

With a large proportion of its population now triple-vaccinated, Israel seems to have broken the fourth wave. A recently published analysis shows the effect of the booster campaign, with protection for recipients of the third dose now restored to a highly satisfactory 93-percent level.

The data we have gathered had already indicated the dwindling protection afforded by the vaccines, and what we already suspected has now been confirmed by the latest analyses and studies. The third jab is not “just” a booster per se, but rather complements the vaccination series. According to our data, a third dose of the vaccine finesses immunity and completes the vaccination protection. The antibodies after a third shot are usually in a range that cannot be achieved by just two. This means that, even if vaccine efficacy slowly declines again after a third dose (and it will), it does so from a higher baseline and thus probably more slowly. We are working on the assumption that “fully vaccinated” status will soon no longer apply to those who have had only two doses. How policymakers and governments react to this remains to be seen.
Vaccine breakthroughs are becoming an increasingly acute problem, and booster vaccination is currently the only way to tackle it. The more people, especially the elderly, receive booster vaccinations, the more we will be able to flatten out the wave. In our opinion, countries that have a vaccination rate below 70% and in which the population received their first and second vaccinations early are at a disadvantage in this scenario. The recommendations we make to our clients will continue to be on an individual and, above all, laboratory-dependent basis. This means that we look at the overall picture of antibody quantity and quality, T‑cell immunity and general immune system status. Our recommendations are therefore not country-dependent and may therefore not necessarily be in accordance with national rules and regulations.

We expect that the future will bring more opportunities to recommend full protection against Covid-19. Although vaccination is currently our main pillar of defense, we expect that other methods such as approved antiviral drugs, more effective antibody therapies and differentiated vaccination regimens will be increasingly incorporated into the protection program in the near future.

Dr Robert Hess: Antiviral drugs – One more strategic option in the fight against SARS-CoV-2.

Dr Robert Hess – 11/12/2021

Dr Robert Hess: Antiviral drugs – One more strategic option in the fight against SARS-CoV-2.

The development of effective drugs against COVID-19 has lagged behind that of vaccines. Recently, however, two major manufacturers have reported promising results from studies they have conducted. The UK has already granted approval to one of the new drugs. We assess the current state of play below.

On 4th November 2021, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) gave official approval to the world’s first tablet for treating persons infected with COVID-19. The antiviral drug molnupiravir, was developed by the pharmaceutical giant Merck Sharp & Dohme. This was followed one day later by an announcement from US-based competitor Pfizer that its paxlovid anti-corona pill had also shown high efficacy in interim clinical tests. Pfizer is now also trying to get its own offering approved quickly.

Just how effective are the new anti-corona drugs?

According to Pfizer, paxlovid, which is used in combination with an older antiviral drug called ritonavir, is very successful in preventing severe disease progression in high-risk patients. An interim analysis of test results showed that the drug reduced the risk of hospitalization and death by 89 percent in COVID-19 patients. This rate of success applied to cases where treatment was given within three days of the first COVID-19 symptoms manifesting themselves; similar encouraging results were observed for treatment within five days of the first symptoms appearing.

According to the preliminary results, paxlovid would appear to be more effective than Merck Sharp & Dohme’s molnupiravir. On the basis of a clinical study conducted by the manufacturer, this drug is claimed to reduce the risk of hospitalization and a fatal outcome by 50%, i.e. half of the rate for untreated patients. The drug has been approved in the UK for individuals who have at least one risk factor for succumbing to a severe course of the disease; these include a weakened or suppressed immune system, obesity, advanced age, diabetes and heart disease. The MHRA recommends that the medicament is administered within five days of the onset of symptoms.

How do the new antiviral drugs work?

Paxlovid belongs to the class of protease inhibitors. The active substance blocks an enzyme that SARS-CoV-2 needs to multiply. As a result, the virus cannot replicate itself in the cell and is therefore not able to infect any other cells. The viral load is thus very quickly reduced.

Molnupiravir from Merck has a different mechanism of action, which is designed to introduce errors into the gene code of the virus during replication. These mutations remove the virus’s ability to reproduce further. Because molnupiravir and paxlovid attack viral replication at different sites, it might even be possible to combine the two drugs. This is a conceivable scenario for exceptionally severe cases.

What are the advantages of antiviral drugs against COVID-19?

Molnupiravir and paxlovid are administered in pill form. This is a big advantage compared to previous therapy options – both remdesivir (the only drug approved in the EU for the treatment of COVID-19) and monoclonal antibodies have to be administered intravenously. Consequently, administration as a tablet is simpler, easier to manage and more manageable in an outpatient context.

What are the disadvantages of these two anti-corona pills?

Both paxlovid and molnupiravir must be taken in the first three to five days after the first COVID-19 symptoms appear. However, most infected people do not go to the doctor promptly, waiting until they feel really ill. By then, however, it may already be too late for treatment with antiviral tablets. According to Pfizer, paxlovid will not help save a patient who is already in intensive care.

Not much is known about possible side-effects of the tablets at the moment. The only information from Pfizer in this regard is that severe side-effects were less frequent in the treatment group than in the placebo group. This is a good sign for the time being. Before prescribing paxlovid, however, it is necessary to clarify the extent to which the protease inhibitors are compatible with other drugs, especially those that patients have to take because of pre-existing conditions.

When can approval be expected in the EU and the USA?

The European Medicines Agency (EMA) announced at the end of October that it would review the use of molnupiravir. After the drug was approved in the UK, the EMA stated that it now intended to speed up the review process. Molnupiravir is also pending approval in the USA.

In the case of paxlovid, Pfizer had already submitted an application for emergency approval to the US Food and Drug Administration (FDA) in October. The results of the clinical trials are now to be submitted to the FDA as speedily as possible using the fast-track procedure. Because of the impressive results, the trial involving around 1,200 volunteers has been brought to an early conclusion. Although approval is still pending, President Biden has announced that the USA has already placed an advance order for millions of units of the drug. The UK and Israel have also secured their first batches.

Will vaccinations become superfluous after the anti-Corona pills are approved?

The new COVID-19 drugs from Pfizer and Merck are so far no more than another weapon in our armory for combating the pandemic and, for the time being, should not be regarded as a substitute for vaccination. Declining the opportunity to get vaccinated at the moment is not a good option. However, we do not see the current vaccination regime as the ultimate solution.

The current crop of antiviral drugs are intended to treat those who actually contract the disease and do not yet offer any benefit in the area of prevention. The timing is also crucial: antiviral drugs cannot be used to treat patients in intensive care, because they have passed the point at which the medication might have worked. Furthermore, we cannot yet assess the extent to which the virus can be repressed by antiviral drugs or whether it could even form a resistance to their active substances. We know that individual treatments with inhibitors often lead to the development of resistance in viral diseases. For now, we have to wait and see how they complement the vaccines that are already available.

Whether the manufacturers’ claims will be substantiated in the long term remains to be seen. We see two main possibilities for the future, one of which is the familiar route of vaccination. However, provided we make further progress in the research area of antiviral medication, vaccination could recede somewhat into the background over time or become a bridging solution. Because, as we see it at the moment, vaccination is not the ultimate way out of the pandemic. The effect of vaccination does not last long enough to guarantee comprehensive protection, and it cannot be the goal to keep vaccinating the global population against coronavirus every 4-5 months. Vaccination compliance among the general public will decrease over time due to continued vaccine skepticism, vaccine breakthroughs and also undesirable side-effects. This situation could possibly be mitigated with effective antiviral drugs. Currently, antiviral pills are specific, but if it proves possible in the future to produce non-specific broad-spectrum antivirals, this could be a gamechanger.

We will continue to keep an eye on developments in this area and inform you about further research findings.

Dr Robert Hess: In case of Covid-19 infection – overview of current MAB treatment options.

Dr Robert Hess – 11/11/2021

Dr Robert Hess: In case of Covid-19 infection – overview of current MAB treatment options.

Currently, three anti-SARS-CoV-2 MAB products have received Emergency Use Authorization (EUA) from the FDA for the treatment of mild to moderate COVID-19 in non-hospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization. The issuance of an EUA does not constitute FDA approval.

These products are:

– Bamlanivimab plus etesevimab (US manufacturer Eli Lilly): These are neutralizing MABs that bind to different, but overlapping, epitopes in the spike protein RBD of SARS-CoV-2. The distribution of bamlanivimab plus etesevimab was paused in the United States because both the Gamma (P.1) and Beta (B.1.351) variants have reduced susceptibility to bamlanivimab and etesevimab. However, distribution of the agents has been reinstated in states with low rates of these and other variants that have reduced susceptibility to bamlanivimab and etesevimab.

– Casirivimab plus imdevimab: REGEN-COV. These are recombinant human MABs that bind to nonoverlapping epitopes of the spike protein RBD of SARS-CoV-2.

– Sotrovimab. This MAB was originally identified in 2003 from a SARS-CoV survivor. It targets an epitope in the RBD of the spike protein that is conserved between SARS-CoV and SARS-CoV-2.

Post- Exposure Prophylaxis:
The FDA has expanded the EUAs for bamlanivimab plus etesevimab and casirivimab plus imdevimab (REGEN-COV) to authorize their use as post-exposure prophylaxis (PEP) for certain individuals who are at high risk of acquiring SARS-CoV-2 infection and, if infected, are at high risk of progressing to serious illness.

Recommendations and Dosage:
The COVID-19 Treatment Guidelines Panel recommends using one of the anti-SARS-CoV-2 MAB products listed above (listed alphabetically and not in order of preference) to treat non-hospitalized patients with mild to moderate COVID-19 who are at high risk of clinical progression:

Bamlanivimab 700 mg plus etesevimab 1,400 mg administered as an intravenous (IV) infusion in regions where the combined frequency of potentially resistant SARS-CoV-2 variants is low

Casirivimab 600 mg plus imdevimab 600 mg administered as an IV infusion or as subcutaneous (SQ) injections

Sotrovimab 500 mg administered as an IV infusion.

When using anti-SARS-CoV-2 MABs, treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 test and within 10 days of symptom onset.

Monitoring:
The authorized anti-SARS-CoV-2 MABs should be administered by IV infusion or SQ injections and should only be administered in health care settings by qualified health care providers who have immediate access to emergency medical services and medications that treat infusion-related reactions. Patients should be monitored during the IV infusion or SQ injections and for at least 1 hour after the infusion or injections are completed.

This is an overview information sheet. If you find yourself in the position of having a Covid-19 infection or needing MAB therapy, please contact us immediately.
In addition to MAB therapy, there are other factors that need to be considered and therefore it is important that you contact us to help you manage such a situation as best you can.

Dr Robert Hess: What next for the SARS-CoV-2 pandemic?

Dr Robert Hess – 11/02/2021

What next for the SARS-CoV-2 pandemic?

The number of infections worldwide is on the increase, and with it, the number of vaccine breakthroughs. However, it is not only the rising rate of infection that is the root cause of this, but also the waning effect of the vaccines themselves. Nevertheless, individuals without any form of immunization are significantly less protected against COVID‑19 disease, and the mRNA booster jabs seem to be delivering on their promise of offering almost complete protection. There are multiple factors at play here that will continue to occupy our attention this winter. In the meantime, this is how we see the current situation.

How prevalent are vaccine breakthroughs, and has their number increased? The number of vaccine breakthroughs worldwide is increasing. All manufacturers and vaccines are affected. A vaccine breakthrough occurs when a fully vaccinated person contracts a coronavirus infection with clinical symptoms.

According to the weekly report issued by the Robert Koch Institute (RKI), 95,487 fully vaccinated persons in Germany, have already been infected with the coronavirus since February. In the week of 27th September ‑ 24 October alone, almost 41,000 vaccine breakthroughs occurred among 18- to 59-year-olds. Measured across the entire period since the start of the vaccination campaign in Germany, the percentage of vaccine breakthroughs among symptomatic COVID‑19 cases in this age group has risen to 10.9. However, if we look only at the last four weeks, the ratio is significantly higher at 37.5 percent.
Increases can also be observed in the over‑60s age group, where the percentage of vaccine breakthroughs among symptomatic COVID‑19 cases is 16.1 for the period since the start of the vaccination campaign. And when we take the figures from only the last four weeks, this percentage increases to 58.9.
Other European health authorities are also reporting that, in some regions, half of the new infections are among the fully vaccinated, and the trend is unfortunately upwards. According to the UK government, four out of ten new hospital patients currently being admitted for coronavirus infection have been vaccinated.
In the USA, breakthrough infections were studied in six states – California, Colorado, Massachusetts, Oregon, Utah, Vermont and Virginia – as the authorities there collect the most detailed data on the disease. Whether their findings can be extrapolated to the entire USA is therefore unclear, but breakthrough infections in those six states accounted for 18 to 28 percent of registered cases during September. Among those who had been vaccinated, Johnson & Johnson recipients displayed slightly higher rates of vaccine breakthrough and of related deaths. Additionally, those vaccinated with Pfizer-BioNTech had slightly higher rates than recipients of Moderna, which can most likely be attributed to dosage differences.

Which age groups are affected?
Vaccination breakthroughs are occurring in all age groups. The proportion of breakthroughs is highest among individuals over 60 years of age. In both the EU and the USA, it appears that it is mainly older persons who are being hospitalized with the more acute infections, as well as individuals whose immune system is relatively weak or who have some sort of immunodeficiency. According to CDC data, 74 percent of vaccine breakthroughs occur in adults aged 65 and older.

Why are there so many vaccine breakthroughs?
The statistics show that vaccine breakthroughs tend to increase as more people are vaccinated against a particular pathogen. In the case of SARS-CoV-2, however, this is not the only reason, as multiple factors are involved here. Firstly, the virus now has renewed opportunities to spread, because most countries have relaxed their regulations on social distancing and face coverings, and because the northern hemisphere is entering the colder winter months. Secondly, the dominant form of the virus is still the Delta variant which is more contagious than the original “wild type” (i.e. Wuhan) or successor Alpha variant and also more successful in undermining vaccine efficacy.

In our opinion, the reason why vaccine breakthroughs have increased so rapidly, especially in recent weeks, is due to dwindling vaccine protection. Current studies even indicate that protection could be as low as 20 per cent only four months after the second dose of a COVID‑19 vaccine. Although a double dose is effective against the Delta variant, the protection it affords begins to diminish after only 30 days. A British study in August found that the effectiveness of the vaccine dropped to 90%, 85% and 78% after 30, 60 and 90 days, respectively. The data from such studies may vary, but the take-home message is that we too have observed the phenomenon of rapidly declining protection during the regular antibody level checks we perform on our clients. We therefore have to assume that the antibodies developed as a result of vaccination wane more quickly than was previously thought and generally published.

So, what are the causes of vaccine breakthrough?
Weakened immune system and age: An already weakened immune system will often be a decisive factor. This mostly affects cancer patients undergoing chemotherapy, patients with autoimmune diseases or the elderly. Especially in senior citizens, it is often the case that the immune system no longer responds adequately to immunization.

Mutations: Mutations also impair the effectiveness of the vaccine. The aggressive and significantly more contagious Delta variant reduces the efficacy of the vaccines. This is because this mutation is better adapted than its predecessors to evade the antibodies that are formed after vaccination. Although the current crop of vaccines are also effective against the Delta variant, more antibodies are needed to neutralize it.

Waning effect: As with almost all vaccines, the effect wears off after some time. This seems to be happening somewhat faster with the COVID‑19 vaccines than initially thought. Data from Israel gathered around mid-July 2021 was already indicating that the effectiveness of the BioNTech/Pfizer vaccine had begun to diminish. Israel was therefore one of the first countries to recognize the need for a follow-up booster jab. Their data showed that, after three months, antibody concentration was reduced by about half.

So, is vaccination pointless?
No, on the contrary. Vaccination protects against infection and, above all, staves off a severe course of the disease. Even if the protection against infection declines over time, protection against the potentially severe consequences remains. According to the CDC study, vaccinated people are eight times less likely to become infected and 25 times less likely to be hospitalized and/or die. A survey of intensive care units also confirms that most COVID‑19 patients admitted are unvaccinated. Data from the UK and Europe suggests that vaccination affords 90% protection against hospitalization. Among those aged 60 and older, protection against the risk of hospitalization is 86 percent. Corona vaccines protect against a fatal outcome by as much as 98 percent (87 percent in the over-60s). But in any case, the only sensible way to drive down the rising number of infections is to refresh vaccine protection with a booster jab.

How important are booster jabs?
Due to the rising numbers of vaccine breakthroughs, booster vaccination has taken on a new urgency. Some countries fear they will be entering a fourth wave around Christmas time, and governments are appealing to their citizens to get their booster without delay. But the vaccination program is faltering in many places, and the approach taken by individual countries also varies greatly. In Germany, the booster vaccine is so far only recommended for the over-70s and the immunocompromised. On Friday, however, the German health minister spoke out in favor of offering booster vaccination to all citizens. Sweden and the USA currently offer a booster jab to everyone over the age of 65 and the UK to everyone over 50 (as well as the immunocompromised, health workers, the occupationally exposed, etc.). Israel has already completed the majority of its booster vaccinations. The country was already battling a fourth coronavirus wave in the summer but now seems to have survived the immediate crisis. According to the Israeli health authorities, this is mainly due to the widely administered third vaccination against the virus.

Until now, all booster vaccinations have been given at least six months after the second dose of Pfizer/BioNTech or Moderna. The length of this interval is now up for debate, especially in view of rapidly declining antibody levels. Thanks to our capacity for monitoring the individual antibody levels of our clients, we have been able to ascertain that some would benefit from a booster jab as early as four months after the second dose. If the vaccine administered was J&J, a booster is already appropriate after only four weeks. This is an option that we also recommend, as we have found that the antibody gain from vaccination with J&J is insufficient.

With governments adopting so many different approaches and also national graphs peaking at different times, it will be interesting to see what stage the pandemic has reached in different countries two or three months further along the line.

What do initial data on the effectiveness of the Pfizer/BioNTech booster tell us?
The first full study has shown that a third dose of the Pfizer vaccine provides an “excellent” level of immunity. On 21st October, Pfizer/BioNTech shared results from their Phase 3 study involving more than 10,000 volunteers. These showed that the booster jab conferred 95.6 percent efficacy. In the half cohort who did not receive booster vaccination, 109 persons later became symptomatically infected. In the half who had received booster vaccination, this number was only five. It also showed that those who received a third dose of the Pfizer vaccine almost a year after their first two had higher protection against symptomatic infections than those who had received only two doses. An earlier study based on real-world population data from Israel found a similar increase in protection against serious illness.

Scientists believe that a decrease in the protection afforded by the first two doses is more than compensated for by the third. However, this refers only to a complete and exclusive series of Pfizer/BioNTech vaccination; there are no comparable data yet on the effectiveness of a third dose of Pfizer/BioNTech to top up a course of AstraZeneca or J&J. Two further studies on booster vaccines were also published in the October edition of New England Journal of Medicine. One found that antibody levels to the Delta variant increased almost tenfold after a booster shot of the Pfizer vaccine. We too have observed this antibody increase in our clients who had already received a booster vaccination.

The long-term prospects may at first seem somewhat daunting, but the data speak for themselves. SARS-CoV-2 will remain with us for the foreseeable future, and we will therefore have to learn how best to live with it. Although we may have hoped for even more ways to combat the coronavirus at this point, science never sleeps and we expect that there will be more to come in the future, including not only new vaccines but also drugs to treat a COVID‑19 infection. Apart from having a well-armed immune system, our defenses against a SARS-CoV-2 infection are “limited” to the best available vaccines. But this weapon seems to be effective enough when applied correctly and affords satisfactory protection for the time being. The realization that antibody levels decrease more rapidly than expected after a second dose of vaccine came as a surprise to many, but the phenomenon of diminishing protection over time is nothing new and can also be observed with many other vaccines.

Vaccines and subsequent responses by the immune system are under permanent review and subject to reinterpretation. While constant chopping and changing of rules and regulations may not always be entirely understandable and can at times be unsettling and demoralizing, it is the only realistic way to tackle the pandemic. We learn something new every day. The biggest advantage we see for our clients in this context is that we are not only privy to the latest research findings but can also incorporate them directly into our individual client concept. The specific data on each individual enables us to make precisely tailored recommendations regarding optimal protection against COVID‑19 and to use our own A.I. data sets in the process. Especially against the background of faster than expected decline in antibody levels and T-cell immunity, this puts us at an enormous advantage.

As we cannot yet predict how severe the coming winter will be, we would urge you to continue to maintain your immunity by following our general recommendations and taking your individually formulated supplements regularly. We will keep you informed and continue to advise you individually on booster vaccinations. If you have any questions, do not hesitate to contact our team of consultants.

Dr Robert Hess: The flu season is just around the corner

Dr Robert Hess – 10/28/2021

Dr Robert Hess: The flu season is just around the corner: What you need to know about the influenza season in general and high-dose vaccines in particular.

Social distancing, face coverings and strict hygiene controls not only reduced the spread of SARS-CoV-2 last year but also of influenza viruses. Flu activity is currently still at a low level, but nonetheless slightly higher than at this time in previous years. Researchers and authorities in the USA and Europe are predicting that a particularly virulent wave of influenza will hit the northern hemisphere in the winter months of 2021/22 and are therefore advising senior citizens to get a shot of the relatively new high-dose vaccines. What exactly are high-dose vaccines? And what can we expect from this year’s crop of flu vaccines?

Are we really in for a tough flu winter?

When a vaccinated or recovered individual is next exposed to the relevant pathogen, his or her immune system learns to attack in a speedier and more targeted manner. Last year, the flu season failed to materialize, and our immune systems missed out on the annual refresher course in combating the flu. Consequently, the influenza viruses may find it easier to spread this winter. Moreover, in the absence of the customary training, individuals are also less able to defend themselves against the flu because their own immune response is no longer as broad and effective. This is certainly the case for the unvaccinated.

Which flu vaccines will be deployed in the 2021/22 season?

Multiple influenza vaccines from different manufacturers are available in the USA and Europe. All vaccines contain the antigens specified by the WHO. Most licensed influenza vaccines for children and adults are of the inactivated kind, containing “killed” viruses or virus components, the only exception being Fluenz Tetra which is an inhaled live vaccine. The so-called tetravalent (alternatively quadrivalent) influenza vaccines protect against four different virus subtypes, namely H3N2, H1N1 (both of influenza A origin) and the two influenza B pathogens.

In Germany, a high-dose vaccine is now recommended for the first time this season for people aged 60 and above. In the United States, the high-dose flu vaccine has already been available since 2019. Containing four times the number of antigens, it could make a big difference in the coming winter season. Generally, any influenza vaccine takes up to 14 days to build up full protection.

What is the high-dose vaccine?

In Germany, the high-dose influenza vaccine goes by the name of Efluelda and is manufactured by Sanofi-Pasteur. Like the other influenza vaccines being made available this season, Efluelda is of the tetravalent variety and contains the vaccine antigens of the influenza strains as recommended by the World Health Organization. However, the dose of aCommittee on Vaccination (STIKO).ntigens is four times higher than in conventional influenza vaccines (i.e. 60 µg instead of 15 µg of hemagglutinin) for each of the four influenza strains. The EU Commission approved Efluelda for people aged 65 and over in May 2020, which was then extended to everyone aged 60 and over in February 2021. It is therefore fully compliant with the directions of the German Standing Committee on Vaccination (STIKO).

In the USA, Sanofi already markets the high-dose flu vaccine under the name Fluzone High-Dose Quadrivalent Influenza Vaccine. It was approved by the FDA (Food and Drug Administration) in July 2019. Sanofi Pasteur also previously had a high-dose flu vaccine in the USA, but it only protected against three strains of influenza. The trade name was Fluzone High Dose.

Why is a high-dose vaccine recommended for the elderly (60 or 65 years plus)?

Globally, nine out of ten people who are hospitalized or even die from influenza infection are older than 65 years. In the United States, between 70% and 85% of deaths and between 50% and 70% of hospital admissions related to seasonal flu occur in people aged 65 and above. This is partly because the human immune system declines with age. The weakening of the immune system can result in older people no longer responding well to the flu vaccine. The effectiveness of conventional influenza vaccines is as much as one-third lower in this group.

A study published in the New England Journal of Medicine showed that the administration of a high-dose vaccine in this group reduced the number of laboratory-confirmed influenza cases by 24% compared to a standard vaccine. In addition, the risk of hospitalization was reduced by almost 7%. A stronger immune response (i.e. higher antibody levels) was demonstrated, thereby vindicating the use of the vaccine to stimulate an aging immune system.

What about possible side-effects?

Due to its increased strength, a high-dose vaccine has a higher reactogenicity, so that local side-effects at the injection site (pain, redness, swelling) may occur more frequently. The symptoms usually disappear after a few days. As part of an Australian study, scientists conducted a survey on side-effects among almost 20,000 individuals who had received the high-dose vaccine. Around nine percent said they had some sort of reaction to the vaccine. The most common complaints were local pain, swelling with redness, and a high temperature.

Overall, the side-effect rate for the high-dose vaccine was about 30 percent greater than that for the conventional flu vaccine. Yet only 56 out of 20,000 high-dose vaccine recipients felt it was necessary to seek medical attention because of this. It is entirely to be expected that the immune system is stimulated more strongly by an increase in dose. This can be observed with almost all vaccinations. Researchers in European countries such as Germany can also draw on data from the USA, which has already been using the high-dose influenza vaccine for several years without any major problems.

To what extent are the high-dose vaccines compatible with other vaccines?

When injected in combination with other vaccines, the unpleasant side-effects are somewhat more noticeable. According to one study, this is especially true for the pneumococcal vaccine, which is often administered together with the influenza vaccine. The combination tripled the rate of those reporting temporary local pain or high temperature to 18%. When the influenza vaccine was combined with a herpes zoster virus vaccine against shingles, there were no increased side-effects. Regarding concurrent vaccination with a coronavirus vaccine (which is an approved method), we can expect reactions to be more common than when administered separately. However, unpublished data from the UK showed only slightly increased vaccine reactions. The immune response to both pathogens was also not reduced.

What level of protection do flu vaccines offer this year?

There are influenza A and influenza B viruses in circulation. The former are considered particularly dangerous. Influenza A viruses are divided into H3N2 and H1N1 viruses (H stands for the enzyme hemagglutinin and N for neuraminidase, the numerical element denoting different subgroups of the enzymes). Hemagglutinin and neuraminidase are the spikes that protrude from the surface of the virus and the most important recognition features for the defense cells. An immune system trained for H3N2 is therefore less able to defend itself against H1N1 pathogens.

Unfortunately, H3N2 and H1N1 pathogens regularly change details on their spikes, which is one of the reasons why a flu infection or vaccination does not necessarily provide immunity against the pathogens that come around the following season. For vaccine developers, the mutability of the flu virus means that they constantly have to adapt their vaccines.

Because production starts months in advance, the WHO closely monitors flu viruses circulating in more than 150 different geographical locations. Based on the data gathered, the organization identifies the pathogens for which the vaccines have to be formulated. The success of this forecast is variable and is the main reason why the effectiveness of vaccines fluctuates between 10 and 60 percent from season to season. An efficacy of 60% was last achieved in the 2010/11 season; in recent years, the efficacy has been between 30 and 45%.

The same applies to the influenza B viruses, except that they are less prone to change. They are divided into two types, the so-called Yamagata lineage and the Victoria lineage. However, the Yamagata lineage has disappeared from the scene since the pandemic and is possibly extinct.

The accuracy of the forecast for this winter can be gauged from Australian data. The current vaccine seems to protect very well against H1N1 and the B viruses, but for H3N2, the prognosis was less encouraging: according to the Australian Government Department of Health, all 20 H3N2 samples showed significant antigenic differences from the vaccine, indicating that protection against H3N2 could be in the low percentage range.

If you have any further questions on this topic or are unsure which flu vaccine you should choose (or indeed whether you should get vaccinated at all against influenza), please do not hesitate to get in touch with us. In the case of individual clients for whom we strongly recommend a high-dose vaccine, we will be contacting them privately.

Dr Robert Hess: Could the Novavax vaccine candidate be a viable

Dr Robert Hess – 10/22/2021

Dr Robert Hess: Could the Novavax vaccine candidate be a viable alternative for skeptics wary of mRNA technology? We take a look at new data on the protein-based inactivated vaccine.

Many people who are skeptical of mRNA technology have been waiting for a conventional vaccine against coronavirus to come along. “Classic” vaccines are traditionally based on proteins. However, the one formulated by Novavax has a major disadvantage, specifically its ability to provide long-term protection against virus variants.

On 10th October, scientists presented the results of a Phase 3 trial involving almost 30,000 adults resident in the USA and Mexico. In the preprint, they report an efficacy of 90.4 percent against symptomatic infection with SARS-CoV-2. In September, the New England Journal of Medicine published results from a trial involving 15,000 volunteers in the UK which came to the same conclusion. Both studies were conducted before the Delta variant became the dominant form of the virus. It was observed that the direct side-effects of vaccination in the Phase 3 study were less noticeable with the Novavax candidate than with the mRNA vaccines. Novavax is also injected in two doses. Among the manufacturers of protein-based vaccines, the US pharmaceuticals giant is the furthest along in the approval process; its application has been running in the EU rolling review process since February of this year. The EU Commission has secured 200 million doses in anticipation of approval. Novavax plans to submit an application for approval of its vaccine in the USA this year. This was the state of play as of 15th October 2021. On closer inspection, however, the Novavax vaccine is somewhat less than conventional. The company itself makes reference to “innovative proprietary recombinant nanoparticle technology.” Although NVX-CoV2373 is a “killed” (i.e. inactivated) vaccine and is thus consistent with an established vaccination principle, it has also been given a new type of adjuvant to boost its effectiveness. This is based on a saponin extract obtained from the soap bark tree native to Chile. It is significant that the COVID-19 vaccines approved so far do not contain an active adjuvant.

The vaccine is produced in insect cell cultures, with up to 14 SARS-CoV-2 spike proteins being combined to form a nanoparticle which, for the immune system, resembles the virus itself. But the nanoparticle does not contain any genetic material – which is not only an advantage, but also a problem. This is because RNA or DNA content strengthens the immune response. This is part of the natural defense against infection, because regular pathogens also contain genetic material.

The adjuvant of the protein-based Novavax vaccine is apparently very effective, as indicated by the high efficacy in the studies. However, it cannot solve one problem of protein vaccines: they neither penetrate body cells nor do the multiply there. This means that the stimulation of the second arm of our immune system – the cellular immune defense – does not take place.

Vaccination can initiate a cellular immune defense response (T-killer cells, memory cells) as long as the vaccine enters body cells, something that Vector and mRNA vaccines are capable of. With protein-based vaccines, on the other hand, the cytotoxic T-cells are only marginally stimulated, with the main thrust coming in the form of antibody response. This makes it easier for the virus to become resistant to these vaccines because the immune response is not as broad.

This may also explain the results of a phase 3 trial in South Africa, where the efficacy of the Novavax vaccine NVX-CoV2373 against symptomatic SARS-CoV-2 infections was only around 50 per cent – possibly because of the local dominance of SARS-Cov-2 Beta which is the most efficient variant at evading neutralizing antibodies.

There are still some gaps in our knowledge about the various Covid-19 protein-based vaccines on the horizon. Furthermore, Novavax currently seems to be having problems with its manufacturing process. It is not yet clear if and when approval will be granted, but we will continue to monitor developments. We expect more news on this front in early 2022. Also on our radar is the vaccine from the French-Austrian company Valneva. They too have recently published the results of a Phase 3 trial of their inactivated vaccine VLA2001 and are likely to submit an application for marketing authorization soon.

By contrast, we already have extensive knowledge about mRNA vaccines. They are safe and have the best efficacy rate. In our opinion, there is no good reason to wait for future marketing authorizations before getting vaccinated.

Dr Robert Hess: Evidence that Delta does not make children more ill

Dr Robert Hess – 10/20/2021

Dr Robert Hess: Evidence that Delta does not make children more ill than other variants of the coronavirus.

The Delta variant of coronavirus does not appear to lead to a more severe course of disease in children than earlier forms of the virus, such as the Alpha or Beta variants. This finding emerged from a prospective symptom study conducted in the UK, in which British school-aged children were compared for symptomatic COVID-19 courses over different time periods.

Study results coming in earlier this year had already indicated that the Alpha variant of the SARS-CoV-2 virus does not appear to make children more ill than the “wild” form of the virus which first appeared in China. The prospective COVID-19 symptom study, the results of which were published last week, compared two groups of school-aged children with confirmed SARS-CoV-2 infection: 694 children infected with the Alpha variant between late December 2020 and early May 2021, and 706 children infected with the Delta variant between late May and early July.

Disease profiles (prevalence of symptoms, duration and sevon the course taken by the disease. erity), hospitalization and presence of prolonged (≥ 28 days) illness were assessed. In both groups, half of the children were ill for no longer than five days. Although the Delta variant displayed slightly more symptoms than the Alpha, especially in older children, this was offset by a similar duration of symptoms, whether these were considered individually or for the illness as a whole. Furthermore, very few children in either group required hospitalization, and long periods of illness were rare. The study was, however, limited by the lack of information on differences between the groups that might have influenced the results, such as whether lockdowns were in force and the impact of different seasons on the course taken by the disease.

However, the data suggests that the clinical symptoms of COVID-19 caused by the Delta variant in children are broadly comparable to those of the disease caused by other variants. This also appears to be consistent with data from the US Centers for Disease Control and Prevention (CDC). That is to say, although we are seeing more cases in children, the severity of the disease is not increasing. The reason why more children are contracting COVID-19 is mainly because there are more COVID-19 cases in the population as a whole.

The study contributes quantitative information to the debate on whether there are significant clinical differences in COVID-19 due to the Alpha and Delta variants, and to the discussion on whether it is appropriate or necessary to vaccinate children (especially those in the younger age bracket) against SARS-CoV-2. We will continue to monitor developments here, especially with regard to new approvals for the vaccination of children.

Dr Robert Hess: Booster jabs are contributing

Dr Robert Hess – 10/08/2021

Dr Robert Hess: Booster jabs are contributing to the individualization of the vaccination concept: Weighing up the potential side-effects of the Covid-19 vaccines and deciding the “price” we are willing to pay.

As winter approaches in the northern hemisphere, booster vaccinations are being rolled out with the aim of giving maximum protection to the elderly, the immunocompromised and professionals exposed to the virus. The administration of booster jabs against Covid-19 is a new concept and one that is likely to be with us for the foreseeable future, as the efficacy of the vaccines against Covid-19 wears off over time. According to the manufacturer of the Pfizer/BioNTech vaccine, it loses approximately six percent of its effectiveness every two months, but our experience has shown that this is a conservative estimate.

This is a game changer, as we are no longer dealing with primary protection, but rather with the boosting of immune status which is composed of antibodies, T-cell reactions and much more besides. However, this attempt at maintenance also entails certain risks. Although the documentary evidence for short-term side-effects of booster vaccination does not give cause for concern so far, we cannot yet clearly assess what the cumulative effect of repeated vaccine doses on our bodies might be in the long term. Repetitive vaccination (and we are not just talking about SARS-CoV-2) puts everyone at increased risk of an adverse dose reaction, for example in the form of anaphylaxis. The bioaccumulation of LNPs (= lipid nanoparticles, an adjuvant of the mRNA vaccines, which enclose the RNA and transport it) could also trigger immune reactions, a potential outcome that is becoming ever more relevant with the booster shots.

All of these considerations have to be weighed up against the alternative: absolute renunciation of the booster vaccine could mean accepting the risk of infection with Covid-19 and possible long-term sequelae. There are, of course, no circumstances under which death from Covid-19 is an acceptable risk, but the long-term consequential damage from Long Covid may well be such. Along with permanent optimization of the immune system, vaccination is currently the most potent means of strengthening our immune status.

In summary, we wish to make you aware that, with every vaccine dose you receive, there is a certain “price” to be paid. This can range from minimal side-effects to hypersensitivity reactions, triggering of autoimmune diseases and symptoms of toxicity. How high this price ultimately goes and whether we should consider it reasonable is not always obvious and is a matter for each individual to decide. Depending on age, immune status and various other factors, the recommendation will vary. Our SARS-CoV-2 Task Force will continue to use your data analyses and our A.I. system to advise on the acceptable “price” (i.e. level of risk) for you.