Pandemic Journal Dr Robert Hess Archive

Dr Robert Hess: Corona drug molnupiravir

Dr Robert Hess – 10/05/2021

Dr Robert Hess: Corona drug molnupiravir significantly reduces number of severe cases of disease and raises hopes, says manufacturer.

Merck Sharp and Dohme (MSD), the US pharmaceutical giant based in Kenilworth, New York, last week reported positive results from a Phase III trial of its new corona drug, molnupiravir. The manufacturer claim that it alleviates the course of the COVID-19 disease and halves the risk of hospitalization or death from a coronavirus infection. The potentially groundbreaking results promise a new way of treating COVID-19 and herald the first of hopefully many more antiviral drugs.

Until now, COVID-19 has been treated with steroids such as dexamethasone and intravenous antibodies (MAB). Both are administered to patients who are already extremely ill. This is not the case with molnupiravir: according to the manufacturer, the medication helps most when it is taken within five days of the onset of symptoms, i.e. in the early phase of the disease.

Molnupiravir has not yet been fully approved, but an Emergency Use Authorization (EUA) from the FDA is expected. Could this antiviral pill bring the world a little closer to normal again?

What is molnupiravir and what are its origins? Molnupiravir was initially developed for the treatment of flu, but has not yet made it to the approval stage for this particular disease. The medication was developed at Emory University in Atlanta, Georgia, in the course of drug discovery research, and in late July 2020, Merck and Ridgeback Biotherapeutics announced plans to study the efficacy of molnupiravir against COVID-19 in trials that would begin in September 2020. On 19th October 2020, Merck then commenced the one-year Phase II/III study of hospitalized COVID-19 patients in the United States.

Molnupiravir itself is a prodrug of N4‑hydroxycytidine, a long-established virustatic agent. As early as the 1970s, scientists were studying the effectiveness of N4‑hydroxycytidine against smallpox viruses. N4‑hydroxycytidine is a ribonucleoside analogue that is inserted into the viral RNA as a “bad” building block, which leads to considerable errors in the copying process with the RNA polymerase (a protein complex that initiates the formation of RNA on the basis of an RNA or DNA template). The mechanism of action is similar to that of the nucleotide analogue remdesivir. However, the effects seem to be more pronounced. The researchers observed lethal viral mutagenesis with catastrophic consequences for the virus (RNA virus error catastrophe). N4‑hydroxycytidine is claimed to be effective against coronaviruses such as SARS-CoV, MERS-CoV and SARS-CoV-2.

What do the results of the trials tell us? The Phase 1 trial of molnupiravir was conducted by the Miami-based manufacturer Ridgeback Biotherapeutics, which had acquired the rights to molnupiravir from Emory University. Molnupiravir was tested on healthy volunteers at a center in the UK at a single ascending dose of 50 to 1,600 mg. No serious adverse events occurred.

Molnupiravir was then tested in a Phase 2 trial on 202 patients who had been infected with SARS-CoV-2 but had only mild COVID-19 symptoms. Patients were given 200 mg to 800 mg of either molnupiravir or a placebo twice daily for five days. At the end of this 5-day period, all patients who had taken tablets containing 400 mg or 800 mg of molnupiravir were virus-free, while the smear test in the placebo group was positive in 11% of patients. As in the Phase 1 trial, molnupiravir was well tolerated. The rate of treatment-induced or serious side-effects was not higher than in the placebo group.

Merck (MSD) has since acquired the license and is currently investigating molnupiravir in multiple international Phase 3 trials at 170 separate centers. The MOVe-OUT trial involved 775 patients displaying mild to moderate COVID-19 symptoms, whose infection had been confirmed no more than five days before. All patients had at least one risk factor for adverse disease progression such as obesity, old age, diabetes mellitus or heart disease. Patients were randomized to five days of treatment with either molnupiravir or a placebo.

An interim analysis in early August found that molnupiravir had reduced the risk of hospitalization or death by around 50%. According to the manufacturer’s press release, this primary endpoint occurred in 28 out of 385 patients (7.3%) in the molnupiravir group as compared with 53 out of 377 patients (14.1%) in the placebo group. There were no deaths in the molnupiravir group compared with eight deaths in the placebo group, so that continuation of the trial was suspended after consultation with the FDA.

What are current expectations? Based on the above results, the manufacturer Merck (MSD) hopes for an emergency approval (EUA) in the near future. Corresponding applications are also to be submitted to other regulatory authorities worldwide. If the medication is approved by the US Food and Drug Administration (FDA), the US government plans to purchase 1.7 million doses.

According to MSD, the company could produce ten million doses by the end of the year. MSD has already entered into licensing agreements with five Indian generic manufacturers, which means that the drug could be made available quickly in large quantities if it is successful.

The latest results from the Phase 3 trial look very promising. The fact that molnupiravir is a drug that is most effective in the early phase of the disease is also a great advantage. We are working on the assumption that the results of the trials will indeed lead to an EUA from the FDA. When this will come is not yet entirely foreseeable, especially since the data have not yet been published and subjected to peer review.

We will continue to keep an eye on what is happening and keep you informed about this. We will also find out when the drug would be available at the earliest and whether it might make sense to be able to have access to it in the event of an infection. Depending on your personal situation, we will contact you again individually as soon as this drug is approved.

Dr Robert Hess: FDA approves booster

Dr Robert Hess – 09/29/2021

Dr Robert Hess: FDA approves booster dose of Pfizer-BioNTech vaccine for the over-65s and for vulnerable categories but not yet for the wider population.

The issue of booster vaccination has risen high on the agenda, and every country is taking a different approach to it. Israel, Austria and Russia are already offering booster jabs to the general population, whereas Belgium, the United Kingdom, Denmark, Finland, France, Ireland, Italy, Spain and Sweden are restricting them to the immunocompromised or elderly. Germany will reach its own national decision in early October, and in the United States, the FDA announced last week that it had approved boosters, albeit on a more restrictive basis than had been expected.

On 22nd September 2021, the FDA issued Emergency Use Authorization (EUA) for the booster dose of Pfizer-BioNTech’s COVID-19 vaccine, but only for certain population groups. The FDA’s decision not to extend the scheme (at least for the moment) to the general population or to all persons aged 16 and older came as a direct rebuff to the announcement from the Biden administration in August that boosters would become available to all eligible Americans starting in late September. It remains to be seen whether this extension of coverage will now happen. At the beginning of last week, the Key Vaccine Advisory Committee voted by a majority of 16-2 against a third vaccination for younger groups of people because of uncertainty as to whether it could be justified in the absence of firm data.

The approval granted by the FDA to the booster vaccination is limited to the following groups of people:

– persons aged 65 years and older;
– persons aged 18 to 64 years for whom who a severe course of the COVID-19 disease poses a significant risk; and
– persons aged 18 to 64 years who are at high risk of severe COVID-19 complications due to occupational exposure to SARS-CoV-2, such as health care workers, teachers etc.

The CDC made known its own booster vaccination recommendation on 23rd September, which is broadly consistent with the terms of approval granted by the FDA. The CDC further recommends that people aged 50-64 years with an underlying health condition should also receive a booster shot of the Pfizer-BioNTech vaccine.

They also advise that, depending on the balance of individual benefit and risk, people aged 18- 49 with an underlying health condition should also receive a booster shot of the Pfizer-BioNTech vaccine. The roll-out of Pfizer-BioNTech booster vaccinations will now begin quite soon in the United States. The single booster jab is to be administered no earlier than six months after completion of the Pfizer-BioNTech primary series (i.e. the first two doses of COVID-19 vaccine). Moreover, the approval of the booster vaccination only applies to the Pfizer-BioNTech vaccine and does not cover the Moderna or J&J alternatives.

The FDA and CDC have thus laid down a guideline, which we will also follow as far as possible. While booster vaccination undoubtedly makes sense for individuals who have passed a certain age threshold or whose physical constitution warrants and/or allows it, different criteria apply to younger age groups. This is the precise reason why we operate on the individuality principle, answering this question on an individual basis for anyone who does not specifically find themselves in one of the above-mentioned groups. If you have any questions or comments, please do not hesitate to contact one of our SARS-CoV-2 Task Force consultants.

Dr Robert Hess: A first step in the right direction

Dr Robert Hess – 09/21/2021

Dr Robert Hess: A first step in the right direction: BioNTech introduces the “individualization” concept into vaccination strategy.

Where are we now, almost two years into the pandemic? Nine months after the first vaccines for the prevention of Covid-19 were approved, are there any conclusions that can be reliably drawn? Since December 2020, 2.39 billion people worldwide have been vaccinated against Covid-19, with a total of 5.82 billion doses having been administered. Just under 30% of the world’s population has thus been fully vaccinated, and in the United States that figure has now passed the 50% mark.

The raw data on how well the vaccines perform against infection with Covid-19 and on whether they provide sufficient protection are well known. Vaccinated individuals are less likely to become infected and, if they should nonetheless contract the virus, the course of the disease is generally much less severe. These statistics are enough to persuade most people, despite the acknowledged risk of vaccine side-effects. So, how are we to weigh up the advantages of vaccination in preventing a disease that can cause long-term harm and even death against the possible side-effects? This is the dilemma in which a large proportion of the population find themselves, depending on age, pre-existing conditions and personal conviction.

In the current circumstances, it is difficult to find the objective middle ground, as there are many different perspectives on the matter. On the one hand, we are currently witnessing a mass clinical trial, in which all those who line up for vaccination are effectively test subjects, and the scientific community is on standby to respond to any side-effects that manifest themselves. These side-effects range from minor local reactions and discomfort after injection to fever, pain, nausea, swelling of the lymph nodes, sensory disturbances, autoimmune disorders and blood clotting. One of the most recent findings was an increased incidence of myocarditis (inflammation of the heart muscle) or pericarditis (inflammation of the tissue that surrounds the heart) associated with a second dose of an mRNA vaccine, an occurrence more frequently observed in adolescent males. This again highlights the potential severity of such side-effects and also the importance of meticulously thorough monitoring.

On the other hand, we are approaching the point where the sheer number of vaccine doses and the thoroughness of monitoring make the detection of further rare diseases increasingly unlikely. Reliable data is available for the elderly who were vaccinated first in the USA, Europe and elsewhere. Nevertheless, there are always the “unknown unknowns”. In other words, vaccines against Covid-19 could theoretically set in motion internal processes that we could not have anticipated. For the moment, at least, the vaccines are safe and surprisingly effective, but what about three years further down the road? We cannot know today what the long-term results will be. The current crop of vaccines are based on an entirely new scientific principle which we are only just beginning to understand. So the question arises as to which groups of people should they be used on? It’s like this: if you are 60 years old, you won’t want to take the approximately one percent risk of dying from corona. In the case of children or unborn fetuses who still have their whole life ahead of them, however, the possibility of long-term complications is a major consideration.

Dr Robert Hess believes that this dilemma should be tackled by means of a specific strategy, with the key concept being “individualization”. The current aim of governments and of the World Health Organization is to vaccinate as many people as possible and thereby maximize protection against infection with SARS‑CoV‑2. Yet this is supposed to happen in a world where individuality counts for more than at any time in history. This issue, which is at the very least defined by differences in age, gender and ethnicity is largely ignored. A structured and finely-tuned individualization plan, such as the one Dr Robert Hess creates, would not only identify risk groups and thus avoid vaccination side-effects, but would also have a positive effect on vaccination success and help to reassure those elements of society who are vehemently opposed. Our individualization plan comprises analysis of age, sex, medical history, risk factors and exposure, vaccine dose and immune status, as well as T-cell immunity and antibody titers against SARS‑CoV‑2.

A strategy of individualization has not yet been introduced on a broad scale, as the focus of the vaccination campaign is currently on the total number of doses administered rather than on the welfare of the individual. Which is not surprising, as there are limitations on the extent to which a policy of individualization can be implemented.

We were therefore delighted to learn last week that the BioNTech team have taken the first step towards individualization in their vaccination concept, specifically in terms of dose adjustment. BioNTech plans to apply for approval of its corona vaccine for children between the ages of five and eleven in the coming weeks. The data for this should be available by the end of September. The dose for this age group will be ten micrograms, which is one third of that given to adults. The data for even younger children (aged 6 months to 4 years) should be available towards the end of the year. Here, too, they expect that the dose can be further lowered.

The study results are already available and must now be finalized for submission to the regulatory authorities. The European Medicines Agency (EMA) has stated that it cannot yet give a timeframe for possible approval. However, BioNTech is already preparing the production of the vaccine doses, so that the vaccination of children between five and eleven years of age could start as early as mid-October. Clinical trials are underway in the USA for both the Pfizer/BioNTech and Moderna vaccines. Previously, there had been delays because the FDA had required a greater number of child participants in the clinical trials being conducted by both BioNTech and Moderna.

According to immunologist Anthony Fauci, the vaccination of children in the States could begin in late autumn or early winter. For younger children, it may take a little longer, as the age groups six months to two years and two to five years are being tested separately. In late July, Israel became the first and so far only country to give the green light for BioNTech/Pfizer to be administered to children in the five to 11 age range who are at risk of serious health complications such as brain, heart or lung problems.

The Pfizer/BioNTech vaccine has been licensed for administration to children aged 12 and upwards since the end of May 2021, and the Moderna vaccine for the same age group since July 2021, but to date there is no vaccine specifically for children, particularly those in the 0-12 age group, which is why the dose adjustment announced now and further clinical research in the field is so important. Possible late complications of vaccination and undesirable side-effects in children can thus be counteracted.

In summary, we can say that we are looking forward to this development and will continue to follow it with great interest. It makes us all the more convinced of the importance and benefits of the individualization program, and we will continue to use this as the basis for our analyses and recommendations of Dr Robert Hess. If you have any further questions about our strategy and our individualization program, please do not hesitate to contact one of Dr Robert Hess consultants.

Dr Robert Hess: Current status and news of new concepts

Dr Robert Hess – 09/16/2021

Dr Robert Hess: Current status and news of new concepts such as antibody therapy and vaccination by inhalation against COVID-19 infection.

Dr Robert Hess has a special interest in this topic, because for some of our premium members the conventional vaccination against Covid-19 is not an option or even can be counterproductive. We see these new concepts as possible solutions for additional protection against coronavirus infection without the need for vaccination.

In certain cases, monoclonal antibodies (MAK) are considered to be a promising drug against severe disease progression in SARS-CoV-2 infection and have been used in the clinical setting for some time. In this context, we are particularly interested in the question of whether and, if so, when antibody therapy might also be used in the context of prophylaxis against a covid infection.

What exactly are monoclonal antibodies (MAK)?

Monoclonal antibodies (MAK) against the SARS-CoV-2 coronavirus are proteins of the immune system that have been biotechnologically engineered to dock to specific surface structures of the SARS-CoV-2 coronavirus. The engineered antibodies bind structures on the coronavirus or block receptors on human cells, preventing SARS-CoV-2 viruses from entering human cells. MAK-containing drugs may also contain combinations of multiple monoclonal antibodies. Monoclonal antibodies were previously only intended as drugs for early therapy in persons infected with SARS-CoV-2 at risk of a severe course, but in August of this year, the FDA approved the first monoclonal antibody therapy for post-exposure prophylaxis as part of the emergency use authorization (EUA).

The FDA revised the EUA for REGEN-COV, which consists of the monoclonal antibodies casirivimab and imdevimab administered together, authorizing REGEN-COV for emergency use as post-exposure prophylaxis (prevention) for COVID-19 in adults and adolescents (12 years of age and older) who are at high risk of progression to severe COVID-19, including hospitalization or death. It remains the case that REGEN-COV has not been authorized for pre-exposure prophylaxis to prevent COVID-19 (i.e. before being exposed to the SARS-CoV-2 virus) – only after exposure to the virus. REGEN-COV was already approved earlier this year for the treatment of mild-to-moderate COVID-19 in adults and adolescents (12 years of age and older) who have tested positive for SARS-CoV-2 and are at high risk of progression to severe COVID-19, and it remains authorized for that.

The FDA emphasizes that prophylaxis with REGEN-COV is not a substitute for vaccination against COVID-19. REGEN-COV may only be used as post-exposure prophylaxis for adults and adolescents who are:

– at high risk of progression to severe COVID-19, including hospitalization or death, and

– not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, people with immunocompromising conditions, including those taking immunosuppressive medications), and

– have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria or

– who are at high risk of exposure to an individual infected with SARS-CoV-2 because of other individuals in the same institutional setting becoming infected with SARS‑CoV‑2.

How is close contact to an individual infected with SARS-CoV-2 defined?

The CDC defines close contact as someone who has been within six feet of an infected person (laboratory-confirmed or a clinically compatible illness) for a cumulative total of 15 minutes or more over a 24-hour period.

What are the possible side effects of receiving a treatment with monoclonal antibodies, such as REGEN-COV?

The most common side-effects were injection site reactions. The signs and symptoms of injection site reactions which occurred in at least 1% of subjects in the REGEN-COV group were skin redness (erythema), pruritus, and ecchymosis (discoloration of the skin resulting from bleeding underneath, caused by bruising). There were no cases of severe hypersensitivity reactions, or potentially life-threatening allergic reactions such as anaphylaxis.

Vaccination by inhalation:

Inhaled vaccines aren’t unheard of — they exist for other viruses such as flu. But they are a relatively new technology, arriving on the market in the early 2000s. The Covid-19 pandemic, however, requires the largest mass-vaccination campaign in history, which means all options need to be on the table for first-round vaccines and any boosters that may be required. Inhaled vaccines should be easier to administer as well as being more accessible and are claimed to have fewer systemic side-effects.

There are currently several research facilities and drug companies testing and evaluating possible intranasal and inhaled COVID-19 vaccines. CanSino Biologics, a Chinese drug company; just finished their phase 1 clinical trial on the world’s first aerosolized adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) and announced its safety and effectiveness after administration of two doses. Phase 2 clinical studies of the vaccine are ongoing.

In the UK, scientists at the University of Oxford have begun phase 1 clinical trials on 54 healthy adults to investigate intranasal vaccination with Covishield following positive findings from studies done on hamsters, while Codagenix, a biotech startup, is currently evaluating a novel inhaled COVID-19 vaccine candidate called COVI-VAC in phase 1 clinical trials involving 48 participants. COVI-VAC is a single-dose, intranasal, live-attenuated vaccine against COVID-19. Unlike many other COVID-19 vaccines, COVI-VAC is designed to produce immunity against all SARS-CoV-2 proteins, not just the spike surface protein, positioning it to protect against a range of SARS-CoV-2 strains.

And in the US, the startups Phage Novo Bio and Precision Virologics have also shown through animal trials that their inhaled candidates for Covid-19 vaccines were safe and effective. In a new study assessing the potential of a single-dose intranasal COVID-19 vaccine, a team from the University of Iowa found that the vaccine fully protects mice against lethal COVID-19 infection. The vaccine also blocks animal-to-animal transmission of the virus.

So far, all of the inhaled Covid-19 vaccine candidates are either in the animal testing phase, or the first stages of clinical trials testing the safety and effectiveness of these sprays in a small group of healthy people. We can therefore only provide an overview of this topic but will continue to keep an eye on what is happening. The publications and findings to date seem promising. Ordinarily, it can take years for vaccines to go from early clinical trials to the market. At the moment, drug regulators have accelerated the authorization process by laying out the exact kinds of data companies need to generate to prove their products are safe and effective. The urgency of vaccinating the world may keep these high-speed processes in place to get the much-needed approvals.

Dr Robert Hess: Update on new mutations

Dr Robert Hess – 09/14/2021

Dr Robert Hess: Update on new mutations and what you need to know about COVID-19 variants.

As experts in the field of human and molecular genetics and thus also on the topic of mutations, we provide regular updates and forecasts of where the pandemic might be heading. Recently, new discoveries have come into the frame, so we have summarized these findings for you and added our own assessment.

Several thousand COVID-19 variants exist around the world, but most of them do not change the way the virus acts. So far, only a few mutants have evolved from the original strain that have given the virus an advantage and accelerated the course of the pandemic. Experts are constantly working to figure out which variants we should focus on and how they change the way in which we combat COVID-19. At the moment, there are only a handful of COVID-19 variants that give us cause for concern. The current “variants of concern” (VOCs) all have mutations in the virus’s spike protein, which acts as a key to break into cells and infect them. This is a source of concern because the spike protein from the original version of the virus is what the scientists have used to design all three authorized vaccines. It is also what monoclonal antibody treatments latch on to so the virus is unable to get into your cells, effectively neutralizing the threat. So far, none of these mutations have changed the virus enough to undercut the vaccines. The current VOCs listed by the WHO are Alpha, Beta, Delta and Gamma SARS-Cov-2 variants.

The Delta variant is our biggest concern at the moment. Identified in India in October 2020, it gained dominance quickly after it was first reported in the U.S. in March 2021. In fact, Delta has now spread to such an extent that it has splintered into several subvariants, referred to as “Delta plus”. Delta plus variants have a mutation in the spike protein found in both the Beta and Gamma variants that may help to evade neutralizing antibodies. While around 13% of infections in the U.S. are from Delta plus variants (AY.1, AY.2, and AY.3), they still behave similarly to the Delta variant. The AY.3 subtype is one of the most recent descendants of Delta but among the most notable. Experts suspect that it is potentially better at escaping the immune system. The variant is most dominant in the US where it makes up roughly 9% of all cases. Along with AY.1 and AY.2, it is now also a variant of concern (VOC). Together, the Delta lineages make up 80-95% of sequenced infections in the U.S. Like other VOCs, Delta has multiple mutations in its spike protein. What makes Delta unique is that it is much more efficient at latching onto your cells and is much more contagious. As already stated, Delta is about twice as infectious as the original strain and estimated to be 60% more infectious than Alpha. People infected with the Delta variant have been reported to have viral loads 1,000 times higher than other variants. Besides the above, five variants of interest (VOI) are currently (as of 09/07/2021) listed and followed with special attention: Eta, Iota, Kappa, Lambda und Mu. While the first four have been under special observation for at least one and a half months, Mu was only classified as a variant of interest by the WHO towards the end of August 2021 due to outbreaks in Europe and increasing infections in Colombia and Ecuador, where the Mu variant is responsible for 39% and 13% of COVID-19 infections. Mu was first sequenced in Colombia in January 2021. So far, it has been documented in 39 countries, including the U.S. However, the percentage of COVID-19 cases triggered by the Mu variant in the U.S. has been falling since July, and the Mu variant caused only about 0.2% of COVID-19 infections in the country in the week of 20th ‑ 27th August. What worries scientists is that the Mu mutations could indicate possible resistance to vaccines. Early research from Italy shows Mu is susceptible to antibodies produced by the Pfizer-BioNTech vaccine, but they don’t work as well as they do against the original Wuhan strain or Alpha variant. In addition, the combinations these mutations indicate a risk of immune resistance. Early research from the U.K. found the specific mutations may help Mu escape the immune system. Further studies are needed for an accurate assessment.

While much of the world’s focus has been on the Delta variant of coronavirus, a new variant was identified in South Africa in May 2021. Currently referred to as the C.1.2 variant, it is yet to be called a VOI or VOC by the WHO, but is drawing the attention of scientists due to the number and types of mutations it contains and the speed at which the mutations have occurred. With 59 detected mutations, C.1.2 is reported to be the variant carrying the most mutations since the original “wild” variant emerged in China. The variant has emerged from the C.1 lineage which was one of the coronavirus lineages that dominated during the first wave of infections in South Africa in mid-May 2020. Although levels of the C.1.2 variant are still low among the South African population, it remains a concern to local public health experts and scientists across the world. Currently, Delta remains the dominant variant in Europe, the U.S. and much of the world. For a variant to become dominant it will have to outcompete Delta. That will mean increased transmissibility, being able to bind to human host cells and infect people quicker than Delta currently does. Time will tell whether any of the variants mentioned here will prevail against Delta and, if so, to what extent. The WHO, public health experts and scientists will continue to closely monitor the course of events. We will also continue to keep you informed about any news on this front.

Dr Robert Hess: Second attempt for CureVac: Modified vaccine developed

Dr Robert Hess – 09/08/2021

Dr Robert Hess: Second attempt for CureVac: Modified vaccine developed in collaboration with GSK is in preclinical testing.

CureVac’s first-generation vaccine candidate CVnCoV unfortunately fell by the wayside in mid-June after failing to meet the statistical criteria for success, but there is now news regarding a modified second-generation vaccine candidate, which CureVac has developed in collaboration with British pharmaceutical giant GSK.

Back in February of this year, CureVac and GSK announced a €150 million joint project with the primary objective of developing multivalent vaccine candidates against viral variants. The initial preclinical data for the second-generation vaccine candidate, CV2CoV, was published in May, with the prospect of clinical trials commencing in the third quarter of this year. However, this target was missed, and the data from the preclinical study in non-human primates did not become available until 16th August 2021.

This study compared the immune response and protective efficacy of the first- and second-generation vaccine candidates. The second-generation CV2CoV was found to activate the innate and adaptive immune response better than its first-generation predecessor at the same dose, resulting in a faster onset of immune response, higher antibody titers and stronger activation of memory B and T cells. In addition, CV2CoV achieves greater antibody neutralization of all selected virus variants, including Beta, Delta and Lambda.

Induction of innate immunity was studied on the basis of specific cytokine markers. Adaptive immune responses were assessed according to specific antibodies for the receptor-binding domain and neutralizing antibodies, as well as memory B and T cells. The current preclinical testing of CV2CoV is to be followed by a phase 1 clinical trial commencing in the fourth quarter of 2021.

What exactly is the difference between the first-generation vaccine candidate (CVnCoV) and the second-generation version (CV2Cov)? CV2CoV is currently in the preclinical development stage and, like CVnCoV, consists of non-chemically modified mRNA which has been encoded for the prefusion-stabilized full-spike protein of the SARS-CoV-2 virus and formulated in lipid nanoparticles (LNPs).

However, CV2CoV is based on a newly developed mRNA “backbone” with specifically optimized non-coding regions to allow improved mRNA translation for enhanced and prolonged protein expression in comparison to that of the first-generation mRNA. The dosage of both vaccine candidates has not changed and remains at 12 µg per vaccine vial.

The data on the new CV2CoV vaccine looks promising so far, and if it carries on in this same positive direction, we expect the vaccine to be available sometime in 2022. We will continue to follow developments closely and provide you with any further information as soon as it becomes available.

Dr Robert Hess: Recent studies have established a strong link

Dr Robert Hess – 09/03/2021

Dr Robert Hess: Recent studies have established a strong link between the presence of autoantibodies against interferon-I and a severe progression of disease after infection with SARS-CoV-2.

As we have explained in previous Keynotes, our body’s own interferon system plays an important role in the activation and modulation of the immune defenses. In this update, we will focus on what happens when there is a failure to activate the type I interferons (IFN-I) and on the risks that this poses. IFN-I is of immense importance in relation to the body’s own virus defense and thus highly relevant in the context of the SARS-CoV-2 pandemic.

Current thinking is that the functionality of interferon-I can be inactivated and/or neutralized by two mechanisms in particular: Firstly, a functional restriction can result from a genetic mutation, i.e. depending on the gene sequences in which the changes are located, it can distort the signaling pathway of interferon-I activation and thus weaken resistance to the virus. Studies conducted in 2020 were already able to establish a relationship between gene mutations of the interferon-I pathway and severe courses of the Covid-19 disease.

The second potential factor behind restricted IFN-I functionality are the so-called “autoantibodies”, which have been the focus of research for some time. Originally, it was assumed that autoantibodies were the result of a severe Covid-19 infection, but it is now looking more likely that they are in fact the cause. This realization is based on two independent studies that investigated the prevalence of autoantibodies against IFN-I in the healthy population and the presence of autoantibodies against IFN-I in severely ill Covid-19 patients. It was found that 0.18% of healthy 18- to 69-year-olds had autoantibodies against interferon-I and that this proportion increased with age: autoantibodies were present in approximately 1.1% of 70- to 79-year-olds and in 3.4% of those over 80. In the most recent study conducted in August of this year, scientists tested nearly 4,000 critically ill Covid-19 patients for autoantibodies to IFN-I. Overall, 13.6% of these patients had autoantibodies, ranging from 9.6% in those under 40 to 21% in those over 80. Autoantibodies were also present in 18% of those who died from the disease. Autoantibodies against IFN-I are therefore present to a certain percentage in the entire population, and their number increases with age. Taken in conjunction with other factors, it was therefore to be expected that there would be a connection between older age and a severe course of infection with SARS-CoV-2. Experts therefore recommend that patients suffering from Covid-19 be tested in hospital for potential autoantibodies against IFN-I and IFN-I mutations in order to better assess and predict the course of the infection. The role of autoantibodies – also in relation to other infectious diseases – has not yet been fully explored. We expect that further insightful findings on this topic will emerge from research in the future. As part of the C-19 immunization program, the interferon receptors and their activity level are regularly tested. This allows us to ensure the optimization of interferon receptors and thus improve immune response through therapy suggestions.

Dr Robert Hess: FDA grants full approval to the Pfizer

Dr Robert Hess – 08/25/2021

Dr Robert Hess: FDA grants full approval to the Pfizer/BioNTech COVID-19 vaccine – What exactly does full FDA approval of a vaccine mean?

The Pfizer/BioNTech COVID-19 vaccine first received Emergency Use Authorization (EUA) from the U.S. authorities in mid-December 2020 for administration to persons aged 16 and older. On Monday, the FDA announced that it has now granted full approval. The vaccine has thus become the first to receive FDA approval for use against coronavirus. More are expected to follow in the coming weeks and months. Emergency Use Authorization continues to apply for use on adolescents aged 12 to 15 years and for administration as a third booster dose to immunocompromised individuals. Further monitoring of the vaccine’s safety and efficacy remains mandatory, even after approval, and will be carried out assiduously.

How does full authorization differ from the previous EUA (Emergency Use Authorization)?

For both emergency and full approval of COVID-19 vaccines, the FDA first requires data from Phase 1 trials to determine their safety, as well as possible side-effects and the most effective dosing regimen. Once this is successfully completed, the vaccine is tested for efficacy in a more extensive Phase 2 clinical trial conducted in a controlled setting. It should be mentioned that the number of volunteers in the first COVID-19 safety trials was similar to the number participating in trials for other commonly used vaccines, such as tetanus, diphtheria, whooping cough and meningitis. The difference in the approval procedures lies primarily in the length of time the volunteers remain under surveillance. For emergency approval to be granted, the FDA requires that at least half of the participants in the original trials be followed for at least two months after vaccination, whereas for full FDA approval, participants in the original trials must be followed for at least six months. The vaccine manufacturer is also required to submit more detailed production plans and procedures and to commit to a higher level of monitoring and inspections.

How do vaccine approval procedures in the USA differ from those that apply in Europe?

Unlike the FDA, the European Medicines Agency (EMA) has approved the current crop of coronavirus vaccines within the framework of a conditional EU marketing authorization. This has the advantage over emergency marketing authorization that pharmacovigilance (i.e. drug safety), manufacturer controls and other post-authorization obligations are legally binding and subject to ongoing assessment by the EMA’s scientific committees. At the same time, it allows vaccine developers to submit additional data, even after the marketing authorization has been granted (in contrast to a normal marketing authorization, where all data are submitted before the marketing authorization is granted). In addition, the marketing authorization holder is responsible for the product and its safe use. This is in contrast to the emergency marketing authorization under EU law, whereby the marketing authorization holder is exempt from administrative and civil liability. The vaccine developers Pfizer/BioNTech are therefore fully liable.

How does full FDA vaccine approval differ from other earlier vaccine approvals?

To speed up the process of full vaccine approval, the FDA has adopted a number of different approaches. These include the Priority Review and Fast Track processes, both of which were used in the case of the approval granted to the Pfizer/BioNTech COVID-19 vaccine. The Priority Review designation signifies that the FDA aims to make a decision on an application within six months, compared to the ten-month period that applies with the Standard Review. However, the scientific/medical standards for approval and for the quality of the evidence required remain unchanged. The Fast Track process is intended to speed up the development and testing of medicines and/or vaccines and to make them available to patients sooner. Fast Track status allows companies to submit parts of their authorization application to the FDA for review as soon as these are completed. There is a further expectation that communication between vaccine manufacturers and the FDA will be intensified and a continuous exchange of information will take place.

According to the FDA, the differences between the approval of a COVID-19 vaccine and earlier vaccines lie in the speed of the process and the number of staff deployed. It cannot be ruled out, however, that this acceleration of the process will leave the quality uncompromised, especially with regard to the shortened observation period and the consequent lack of data. We will therefore continue to closely observe the current procedure and any further developments and to keep our Premium clients informed.

Dr Robert Hess: Any decision on whether to receive a booster jab

Dr Robert Hess – 08/17/2021

Dr Robert Hess: Any decision on whether to receive a booster jab (and which one to choose) or to wait for a next-generation vaccine should be based on the following criteria.

1 – Which is preferable – a booster jab or a next-generation vaccine? This depends on a number of factors, primarily which next-generation vaccine becomes available and when. It should be noted that the latest vaccine under development at BioNTech has been formulated exclusively to counter the threat of the Delta variant. We therefore need to carefully monitor how the virus continues to mutate, because the successor to Delta is already on the way. It may even turn out that, by the time the next-generation vaccine is ready for rollout, the current Delta variant is no longer relevant. At this point in time, BioNTech is the only manufacturer to have not only developed a next-generation vaccine but also to have produced an initial batch. However, it has not yet received official approval. Whether and when this is granted by the FDA will not be based on medical criteria, but on political considerations, namely how to persuade the public to receive the 700 million or so doses of the current vaccine if it became common knowledge that the BioNTech next-generation vaccine had already been approved.

2 – When is the moment to act? Before any action is taken, the individual status of each client has to be considered carefully. The three decisive criteria here are the most recent antibody count, the level of T-cell immunity and the general immune response. These reference values are then run through an algorithm by our AI system to determine the optimal timing of any further vaccination. The decisive factor is, of course, the general immune response and whether it is strong enough and operates with pinpoint accuracy in the event of an infection. This is precisely the purpose of our ongoing monitoring. And it is a good reason to keep taking the recommended supplements very regularly, even into the autumn.

3 – What would a sensible vaccination strategy look like? All three of the above criteria should be considered. For example, if T-cell immunity is weak and the first vaccination was with an mRNA-based vaccine, it would make sense to adopt a mix-and-match approach and switch to one of the vector-based vaccines, because these are better at improving T-cell immunity. The problem for our clients in the USA is that the only vector-based vaccine currently approved there is the Johnson & Johnson, and unfortunately, we are not convinced by the version currently available.

4– What else needs to be considered in deciding on further vaccination? A further criterion in taking the next step is the natural limit on the number of doses the human body can cope with in a given period. The underlying problem is that every vaccine, especially those developed to combat SARS-CoV-2, overstimulates the immune response, thereby triggering autoimmune reactions. We are of the opinion that no-one should receive more than 2-3 doses per year of the vaccines so far developed. Assuming that the pandemic will continue for a very long time, it is important to consider exactly when to vaccinate and which vaccine to choose in order to derive the greatest possible benefit. This way, the risk can be avoided of vaccinating too many times in a limited period of time, thereby putting a strain on autoimmune capacity and prompting autoimmune diseases in the future. After a finite number of vaccinations in a set period of time, of course, the autoimmune capacity has increased to such an extent that, at some point, the benefit has to be weighed against the cost. In other words, the harm done is greater than the risk of damage from Long Covid. That is why we have to be cautious about the number of vaccinations we subject ourselves to within a certain period of time.

5 – What are the potential advantages of a booster jab? If your next vaccination is to be a booster jab rather than a next-generation vaccine, then it must be taken into account that the current vaccines from Moderna and BioNTech are both approximately 30‑35% effective in preventing infection by the Delta variant, i.e. a relatively low rate of efficacy. On the other hand, our internal research and our contacts with BioNTech suggest that a third dose of their vaccine boosts antibody levels by a factor of four. In these circumstances, even a 30% success rate is a strong argument in favor.

Over the next few weeks, we will be checking these criteria as they apply to each of our Premium clients, using all available data. At the same time, we will set our A.I. system to calculate the optimum choice and timing on an individual basis. We will then contact you directly. If you have any questions in the meantime, please contact your consultant.

As Dr Robert Hess expected, the pandemic is becoming more complex

Dr Robert Hess – 29/07/2021

As Dr Robert Hess expected, the pandemic is becoming more complex and problematic in nature, which makes it all the more difficult to make any firm predictions for the autumn.

In focus: Vaccine side-effects versus post-acute sequelae (“Long Covid”).

The forecast of Dr Robert Hess in the spring of 2021 that the pandemic would take off in a more complex and problematic direction ran contrary to general opinion. It is now being vindicated even earlier than we expected.

It is definitely not the case that the end of the pandemic is in sight, as claimed by various colleagues as well as some government leaders in May and June of this year. The reduced efficacy of the first-generation vaccines against the recently arrived and now prevalent Delta variant has introduced an element of considerable uncertainty that is also impacting on forecasts for the global economy.

As indicated in the previous Keynote, our current focus in the research we perform on behalf of our clients is on deciding whether their needs are best met by receiving a booster jab or by waiting for a next-generation vaccine to become available and, in either case, what the optimum timing might be.

We have already established reference values in our retesting procedures for antibody development and T-cell immunity, and we are confident that the WHO will adopt similar or even identical values by the end of the year. These are now the clear reference values for all our clients in deciding whether there is a need for action to ensure immunity against the SARS-CoV-2 virus and its mutants. This gives rise to a number of questions that we will clarify individually for each of our clients. The two key questions concern the timing and the choice of vaccine, specifically whether this should be a booster shot of the same vaccine. A third dose of the BioNTech vaccine can have the effect of increasing antibody counts by as much as fivefold. This is an attractive option for those clients who have antibody levels of less than 1,000 BAU/ml and thus far below our reference value.

The alternative is to wait for the next generation of vaccines to become available. As also reported in the previous Keynote, BioNTech has developed a proprietary vaccine to specifically target the Delta variant spike protein. This vaccine has already gone into production and is awaiting emergency approval from the FDA and EMA. Here, too, a fundamental decision must be made – booster or next-generation vaccine? What are the advantages and disadvantages?

The disadvantage of a next-generation vaccination could be that the next virus variant – and we have to assume that this already exists in the form of the Lambda or similar – could produce a change in the spike protein, thereby reducing the effectiveness of the newly developed vaccine, though not as much as that of its predecessors. This is the very race we wrote about several months ago and which is now well and truly underway. Unfortunately, the vaccine manufacturers are still in reaction mode at the moment, having to firefight the variants as and when they crop up. This consumes huge amounts of time and effort.

As to whether we are already on the home straight or only the opening lap of the race against new variants and whether the pace of mutation will pick up even further, Dr Robert Hess shares the general opinion that the odds are currently 50-50. In other words, there is a very real risk that the changes on the spike protein will become even more prominent. This issue carries over into the debate on super mutants.

On the assumption that the rate of mutation will continue to accelerate, this is a race that is going to be difficult to win. We still have the potential offered by artificial intelligence to make predictions about future mutations and thus stay one step ahead of the virus. But the probability of a super mutant has also increased significantly. The definition of a super mutant is that the virus has undergone a genetic change of such magnitude that the current vaccines become less than 20% effective.

The main argument against a third booster jab with the current generation of vaccines is that they are clearly less effective against Delta than against the Alpha variant, even if there are efficacy studies that seem to indicate the opposite. However, the number of people who are being hospitalized despite having been double-vaccinated is rising sharply in virtually all countries. In this matter, we have to disagree with our colleague Anthony Fauci in the USA, who attributes the problem of rising new infections to large numbers of non-vaccinated people becoming infected. This is certainly a major factor, but at the same time, the significantly reduced effectiveness of the vaccines currently in use is also a reason why the infection and hospitalization curves on the graph are heading upwards. In addition, there has been an increase in mortality in countries that have had the Delta variant for some time. The studies from Canada on the link between mortality and Delta as well as the latest data from the UK confirm that the new variant causes the death rate to rise. The scenarios differ slightly, in that the rise in number of cases in England is probably due to a relaxation of social distancing during the recent Euro 2021 Football Championship. But all in all, this is an indeterminate development that is very difficult to interpret.

The deliberations about the Delta variant, which have been going on in Europe for some time, have now also reached the USA. Delta was ignored there for too long, and in the meantime, there are districts in California where masks are once again being made compulsory in enclosed public spaces, even for vaccinated persons. The complexity of the situation is also global in the sense that political decision-makers are reluctant to issue any clear guidance on whether booster jabs or next-generation vaccines are the way ahead. For pandemic management and to achieve herd immunity, it is essential to have clarity on vaccination of children under 12 and teenagers. Because of the exaggerated immune response to vaccination, especially in younger age groups, the appropriate dosage should be based on the same categories that apply with any medicine, namely “Babies”, “Children”, “Adolescents” and “Adults”. These should be introduced as soon as possible as a crucial success factor in pandemic response. This is a move Dr Robert Hess was already calling for a year ago.

The politicians and licensing authorities are showing some reticence in regard to next-generation vaccines, for example the one from BioNTech which is already being developed and produced in Mainz (Germany), because of a fear that the prospect of their arrival in the near future might further reduce take-up of the current generation of vaccines. In almost all countries of the western world, vaccine hesitancy is already high, and the availability of an upgraded Delta vaccine would reduce vaccination acceptance even further. It is therefore a topic of discussion that is not wanted either politically or by the WHO, which is a rather unfortunate state of affairs.

The booster jab is also a politically sensitive topic because the majority of the world’s population does not yet have access to any vaccine at all. Meanwhile, first-world countries such as Israel have already embarked on their third round of vaccination. This imbalance is an added complication to the whole situation, with disturbing consequences such as were witnessed last weekend when vaccine poverty provoked anti-government demonstrations in the emerging countries of Tunisia and Brazil as well as in several Third World countries.

At the same time, the precise opposite phenomenon is manifesting itself in western countries where supplies of vaccines are more than adequate. In France and Italy, for example, there were also mass demonstrations at the weekend, albeit in opposition to mass vaccination. Against this background, it is wholly understandable that the WHO currently opposes booster jabs on principle.

All in all, the issue of booster vaccination has been taken up too late by the political decision-makers. We have been pursuing our retest strategy to continuously monitor the SARS-CoV-2 immunity of our clients since June, which has flagged up a disappointing decrease in antibodies and in T-cell immunity. This came as a surprise even for us, and so we were obliged to consider the issue of booster vaccination sooner than expected. We have therefore decided to make recommendations to our clients regarding booster jab or next-generation vaccine on an individual basis. We aim to be in a position where we can issue appropriate recommendations to our clients by mid-August.

Around the world, governments of all political complexions are steadily moving away from the imposition of mandatory social measures towards the individual taking responsibility for protecting his or her own health and safety and that of others. We intend to provide our clients with an even more focused basis for decision-making. The UK has adopted something of a pioneering role here. We have been very pleasantly surprised that the majority of the population there is behaving prudently and only using their restored freedoms in moderation. We think this is the right approach. Each individual must be allowed to map his or her own route through the pandemic.

It is not surprising that there are still people who do not want to be vaccinated. The main reason for reluctance is the side-effects of vaccination that have been observed so far. Of course, this is only a cautious analysis, because we have to assume that there will be a considerable increase in vaccine-induced autoimmune diseases in the coming years. The relevant data will begin to emerge only gradually. On the other hand, we already know for certain that Long Covid sequelae are more severe and more enduring than the side-effects of the vaccines. In this context, there are more and more warning signs, especially from the FDA and EMA, of capillary leak syndromes associated with the Johnson & Johnson vaccine. This can lead to acute episodes of oedema, mainly in the body extremities and when blood pressure is low. Another alert issued in connection with the Johnson & Johnson vaccine concerns Guillain-Barré syndrome, a rare inflammatory neural disease that may occur around the six-week mark after vaccination. There are also the myocarditis syndromes associated with mRNA vaccinations. Pericarditis, an inflammation of the heart muscle or the pericardium, is more often triggered after the second dose of the vaccine. The first instances of autoimmune disease have now appeared with the Moderna vaccine, specifically immune thrombocytopenia. These cases are being closely studied by both the FDA and the EMA. We see a clear link here with the vaccine. Another side-effect of mRNA vaccination is the occurrence of dermatological problems, namely delayed reactions in the form of skin eczema and hives that are usually associated with urticaria. These are triggered by so-called lipid nanoparticles that serve as a sort of protective packaging for the mRNA. These nanoparticles have the ability to activate the immune defense cells directly, so that large amounts of histamines (i.e. inflammatory messengers) are released. Where urticaria-like reactions occur, this is generally after the second shot of vaccine, and they can lead to severe complications such as asthma.

The AstraZeneca vaccine also contains a substance known as polysorbate 80, which is used as an excipient in some cosmetic medicines and also has considerable allergic potential. For this reason, we recommend heterologous vaccination (i.e. cross-vaccination) as standard, with a first dose of AstraZeneca followed by an mRNA vaccine as the second. Here, too, the vaccine side-effects can be considerable, and much stronger than with a homogeneous vaccination regimen. That is why we only recommend cross-vaccination in older people where immunosenescence (i.e. the gradual deterioration of the immune system brought on by aging) has set in.

The harm caused by Long Covid is much more difficult to assess, and we will discuss it in more detail in the next Keynote. From the data that is now beginning to accumulate, it is apparent that 80% of those who had symptomatic infections continue to feel worse after three months than they did before the onset of the disease. This is an alarmingly high percentage. A variety of check-ups and monitoring activities show that around 20% have sustained clearly detectable organ damage. The age group most affected by organ damage is between 40 – 50 years old, individuals who were previously relatively healthy and had no pre-existing chronic illnesses. Organ damage can even be found among the youngest cohort of 20-year-olds. There is an above-average number of athletes, which is probably down to the fact that the body feels completely different and that the perception of performance loss is therefore naturally felt more keenly. There are also neurological consequences ranging from disorders such as loss of taste, nerve pain and deafness to aphasia, significantly reduced cognitive and cardiological performance, shortness of breath, etc.

Understandably, the main focus of the check-up recommendations we make to our clients is on heart disease. This is because the endothelium in individuals who have survived Covid-19 has undergone massive changes and has essentially aged by many years. This manifests itself in cardiac insufficiency, cardiac arrhythmias and changes in the pulmonary interstitium that inhibit gas exchange and lead to respiratory distress. We will give an update on the consequences of Long Covid in the next Keynote.

As inoculation is a highly complex area, other scientific avenues are being explored involving different techniques. We have looked at three of them in some detail. Two come from a single country, namely Israel. We suspect that, should there ever be a solution that avoids inoculation, for example by means of a virus static, then the Israeli manufacturers will be at the forefront.

First, we looked at the oral Covid-19 vaccines produced by Oravax Medical, a company that specializes in this field. Clinical trials are already underway in Israel. We will monitor this development in detail and report back at a later stage.

The second solution comes from SaNOtize, another Israeli company. It is a so-called “anti-corona nasal spray” containing antibodies obtained from bovine colostrum which has already successfully negotiated clinical phase 2. Here, too, there is hope for success.

The third solution we will be pursuing from a poll of almost 20 companies drawn up by our research team comes from Australia, where CRISPR (clustered regularly interspaced short palindromic repeats) “gene scissors” have been deployed to inactivate the coronavirus. Here, too, the success rate does not look at all bad – it proved relatively easy to stop the SARS-CoV-2 from replicating in an infected cell. The results of the project have been published in Nature Communications magazine. It is an exceptionally interesting project for us because it concerns our own field of expertise, namely genetic engineering. Once the virus is identified, the CRISPR enzyme is activated, which then proceeds to dissect the virus. We will, of course, keep you updated on this development.