Monthly Archives: October 2021

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

Dr Robert HEss

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

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

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

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.

Dr Robert Hess: Corona drug molnupiravir

Dr Robert HEss

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

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.