Dr. Ingo Fricke, is a German immunologist. He has studied chemistry at the University of Marburg. He has specialized in biochemistry and he also did his Master’s thesis in biochemistry working on soil bacteria (B. subtilis) that produce an antibiotic. Later he has shifted his main focus on medical and cancer research. Dr. Fricke has received a scholarship from DFG (German research foundation) and pursued his PhD in immunology/cell biology in immunotherapy of bladder cancer at the Borstel Research Center, near Hamburg. He has researched a white blood cell population called dendritic cells and how they are activated by mycobacterium BCG, which is besides a vaccine strain against tuberculosis also a therapeutic against bladder cancer. To further deepen the knowledge of oncological immunotherapy, Dr. Fricke went for a postdoctoral residency in USA. There he worked at H. Lee Moffitt Cancer Center in the group of Dr. Dmitry Gabrilovich, with main focus on dendritic cells and how cancer evades their recognition. He worked for a medical device company in Hamburg coordinating their immunology research projects with regard to electromagnetic fields. Actually, he is supporting some SARS-CoV-2 projects like the “SARS CoV2 COVID Plan B Task Force”. 

An Interview with Petia Minkova

- Dr. Fricke, You are a very famous immunologist. You observed that all antibody approaches (except one), building on a single antibody against the spike, which again harbours a very high risk of immune escape as was evident i.e. in cancer therapy case. What are your thoughts?

- Thank you that is very kind, I just consider myself an ordinary immunologist. Yes, you are correct we observed first in cancer therapy that using only one monoclonal antibody against one protein (antigen) leads to evolutionary pressure and the loss of susceptibility to this treatment. The pharmaceutical companies repeating this same mistake again with a single monoclonal antibody against SARS-CoV-2 spike protein which is mutating even faster and some of the developed antibodies lost already their function. There are exceptions like Regeneron (REGN-COV2) who use a combination of two different antibodies and VirBiotechnology (VIR-7831, Sotrovimab) that is directed against a functional relevant region and therefore very unlikely to mutate without losing its function.

- You tried to help the world vaccinology that the goal should not only be the spike protein of SARS-CoV-2. What is the real and more effective target?

- Indeed, when I first heard about the new corona virus it immediately peaked my interest, even more so when it was obvious that we are facing a pandemic. I read every research paper about the new virus and started to follow all information on vaccine development and realized that we are very variable when it comes to the platform (mRNA, DNA, viral vector, protein and attenuated virus) used for the vaccine but when it comes to the antigen all use the solely spike. I began writing a paper with a friend , Dr. Scott Nathan Freeman from US (this paper was never actually accepted to be published) and we began warning people in May 2020 that the mainstream vaccine strategy is very likely to produce escape variants and using additional viral envelop proteins could be more appropriate to exert an immune response that resembles more natural immunity.

[1] preprint: https://osf.io/msu98

- Please explain in detail what the most effective SARS-CoV-2 vaccines would be?

- I can’t predict how the most effective vaccines would look like, but in my opinion a better vaccine should contain all of the proteins found in the envelop of the virus which is case SARS-CoV-2 only four, namely the membrane (M), nucleocapsid (N) and envelop (E) to mount a broad immune response which makes it difficult for the virus to escape. One could include also that some other proteins which are crucial for the virus function like RdRp (the enzyme that makes viral proteins from its RNA) or Mpro (main protease) but which are only present once the virus has infected a person (host organism). Platforms that could be used are definitely mRNA and protein vaccines (subunit vaccines) but I don’t know if there are viral vectors that could contain all these proteins at least as far as I know adenovirus has only limited space.

- Everyone is talking about ACE2 as the receptor for SARS-CoV-2 but you also mentioned other receptors.

- Yes, it’s true ACE2 was identified as the receptor for host viral interaction of spike and one gets the impression that once this was established we stopped searching for other receptors but already in May 2020 it was shown by a group in Gottingen that also TMPRSS2 was pivotal . The crystal structure of spike revealed a lot sugar structures (glycosylation pattern) on the surface as one also observes for bacteria, so it was obvious for me that also danger receptors are involved that one not necessarily attributes to viral recognition1. Meanwhile it was shown but doesn’t get much attention that L-SIGN and DC-SIGN promotes virus transfer to permissive cells and can be blocked by a glycomimetic compound (PolyMan26). Also for toll-like-receptor 4 (TLR4) it was shown to bind spike protein and there exist inhibitory drugs like Eritoran (Eisai) and Resartovid (Takeda). These inhibitors are already in clinical phase II and III testing and might have the potential to prevent cytokine storm.

[2] https://www.sciencedirect.com/science/article/pii/S0092867420302294

[3] https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009576

- Isn't the nasal induced immunity a much more direct way to protect the lungs and stop the virus from reproducing?

- Indeed the nose is the doors where the virus enters our bodies and the mucosal tissue in the respiratory tract has some special features to cope with those invaders like a special antibody sort which is secretory IgA (sIgA) which a dimeric form of IgA. The approved vaccines that are intramuscular injection (IM) where shown to produce also IgA to a certain extent. Though the induced IgA is monomeric and not that dimeric form and further is not reaching a concentration in the nasal tract that is needed to eliminate spread of the virus and to make the current vaccines to be sterilizing (truly infection prevention type vaccines).

- What do you think about nasal vaccines? Are they second-generation vaccines? Why none of the medical authorities did not pay attention to the proposals from these scientists and for such new vaccines developments?

- I think a nasal vaccine would be a good fit for a respiratory virus and could be done with any vaccine platform, that’s why we also have suggested it in our preprint (https://osf.io/msu98). Further, there are animal studies showing superiority of nasal vaccines over conventional IM injections. Yes, nasal vaccines could be regarded as second generation vaccines but also all vaccines that induce a broader immunity, meaning that have additional antigens besides spike. Those vaccines are under development and also from the beginning like the one from OSE Immunotherapeutic which uses 15 epitopes or GeoVax who use MVA(Modified Vaccinia Virus Ankara) viral platform to express S & M or ImmunityBio who use S & N in an adenovirus 5 vector platform.

- Why do you think no one is working on nasal vaccines?

- In the meantime there are efforts under way by several companies to tackle nasal vaccines. There is an Indian company Bharat Biotech that is developing a nasal vaccine that is in clinical phase II , also AstraZenca has begun with the development of a nasal vaccine . In clinical phase I trials are US based companies Codagenix and Altimmune, the later will be discontinued due to disappointing trial results. The University of Eastern Finland and University of Helsinki started with a nasal vaccine right from the beginning which was also patent free but started to have funding issues so they had to form a company first .

[4] https://www.business-standard.com/article/current-affairs/booster-dose-bharat-biotech-s-nasal-vaccine-may-be-used-with-covaxin-121092500034_1.html

[5] https://www.science.org/doi/full/10.1126/scitranslmed.abh0755

[6] Codagenix Announces Safety and Immunogenicity Data from Phase 1 COVID-19 Intranasal Vaccine Trial and Intent to Progress to Phase 2/3 Studies (prnewswire.com)

[7] https://news.cision.com/university-of-eastern-finland/r/finnish-researchers-introduce-a-nasal-covid-vaccine,c3301696

- Is it known that nasal vaccines complications and side effects will be much less?

- Side effects are an individual factor, are always observed with a vaccination since one is alerting the immune system and also depend on the on the fitness/health conditions on the vaccination day. For influenza, e.g., there is nasal vaccine approved, namely FluMist, which almost lists the same side effects as the intramuscular one . Some side effects that are caused by the injection surely can be omitted or reduced, but everyone can also do his part in limiting the side effect by i.e. taking Vitamin D3 which will also boost the antibody response exerted by the vaccine.

[8] https://www.medicalnewstoday.com/articles/flumist#about

- Why does every medical authority in each country have chosen intramuscular vaccines, where the path is much more complicated and not so sure that it will reach the final goal?

- This is a very valid question, I myself would like to know, too. So far we made fairly good experiences with intramuscular (IM) vaccines so maybe they acted according to “never change a winning team” approach. Also in the 1990s it was switched from oral polio vaccine (OPV) to IM (IPV) for safety reasons, where OPV was a live attenuated virus whereas IPV is inactivated virus, although IPV vaccinees can still contract and spread the virus. So basically the same as what we are seeing for the SARS-CoV-2 vaccines.

- What do you think when can nasal vaccines appear on the market?

- Very tough question, my rough estimation would be given no delay due to complications in clinical trials and everything go as wanted maybe by end of this year or in the beginning of next year. BBV154 from Bharat Biotech seems to be the furthest progressed candidate and will probably be the first one that reaches.

- What do you think about the idea to vaccinate children (bellow 12 years old)?

- In my opinion healthy children, so children that don’t belong to any risk group like obese, immune compromised etc., are perfectly suited to handle the virus and develop natural immunity without the risk of developing a severe cause of infection or MIS-C and therefore there is no need at the moment to vaccinate these children. So far all known strains do not harbor an increased risk for kids to develop a severe form of COVID or MIS-C. Anyways, it is good to know the vaccine is also suitable for children since we don’t know how this viral evolution will turn out and this standpoint may therefore also change in the opposite direction when healthy children become severely ill due to infection with a new mutant strain.

- In Bulgaria, some medical scientists have reported that after the pandemic is expected a boom in cancer disease? What is your opinion? I ask you because you worked at Borstel Research Center and researched a white blood cell population called dendritic cells and how they are activated by mycobacterium BCG, which is besides a vaccine strain against tuberculosis also a therapeutic against bladder cancer. You know a lot about the immune system, infections, vaccines and cancer and that is why I ask you about it.

How can we plan to protect ourselves in a better way?

- It is well established and known for long time that some viruses are capable to cause some certain form of cancer. The viruses that are definitely linked to cancer are Epstein-Barr (EBV), Hepatitis B (HBV), Hepatis C (HCV), HIV, Herpes virus 8 (HHV-8), human papillomavirus (HPV) and human T-cell leukemia virus type (HTLV-1). To my knowledge there are no reports that betacoronavirus family can cause cancer, meaning I’m not aware of reports linking SARS, MERS or any hCoV to cancer incidents. My assumption would be that it is very likely that SARS-CoV-2 isn’t inducing cancer either, but that isn’t certain so we should observe that situation carefully. On more “connection” between cancer and SARS-CoV-2: some studies about repurposing anticancer treatment for the treatment of COVID-19 are ongoing.

- How can we stimulate the immune system? Please explain in detail if possible? How to create good and effective protection against viruses and COVID-19?

- To stimulated the immune system a variety of measures can be taken and one of the easiest to apply is healthy nutrition and mostly avoid processed or convenience food. As I already mentioned above Vitamin D3 also in combination with Vitamin K2 in the context of vaccine side effects is a great substance to boost the immune system and it has several effects like stabilizing mast cells to prevent excessive degranulation and is linked to the expression of HLA molecules. Also better avoid high fructose corn syrup (HFCS) since a deactivation of vitamin D could be shown in a diet rich in HFCS.

- In your opinion, what percentage of the population is enough to be vaccinated to stop the current corona pandemic?

- I actually don’t know and it seems that with the existing vaccines we don’t reach that point since they don’t convey sterilizing immunity which means limit the spread of the virus. At the moment it looks like we need additional early treatment option (and there are treatment protocols like that of Dr. Shankara Chetty, South Africa) to vaccination and a high vaccination rate isn’t the solution when looking at data from Israel vs i.e. Uttar Pradesh, India. One hypothesis is that when the developed countries hadn’t been so selfish and evenly distributing the vaccine around the world so that all vulnerable groups could have be protected instead of trying to fully vaccinate only a few countries, we will be much better off.

- During this pandemic, most scientists disagreed. Maybe because in some countries healthcare chief medical officer is run by epidemiologists, in others – by virologists, in 3rd cases run by immunologists. Is it possible in subsequent pandemics to make decisions by several (3-4) scientists from different specialties in order to more adequately address the problems from all perspectives and angles?

- We have definitely a lot to learn from this pandemic in many areas and to rethink our established processes. I hope I’m wrong but this wasn’t the last pandemic we are going through and if don’t stop destroying the rain forest and habitats for wild live we will see an increase in spill over cases. Yes, you are right, from my perspective it is very preferable to have team of scientists from different specialties that is advising governments. For example it still don’t understand why we don’t test for T-cells (there are commercial test available) and establish how has had COVID, who has cross-reactive T-cells (first preprint April 2020 ) etc. and that those people don’t need to be vaccinated. To my incomprehension there are even countries that do not acknowledge that natural immunity is protective.

[9] https://www.nature.com/articles/s41586-020-2598-9.pdf

- You analyzed how electromagnetic fields impact the immune cells and the immune system. It is very interesting. Please, tell us more details about this? How about the impact of 5G radiation on the human immune system in the future.

- The goal of the company I worked for was to use low frequency electromagnetic fields for treatment of various kinds of disease and identify the mechanism(s) of action(s). We made good progress in the field of bone healing but preferences shifted in favor to engineering and physics at the expense of immunology. I didn’t follow too extensively the field but in case of 5G a lot of studies are funded by telecommunication companies and one therefor must very cautious with the results. There is no conclusive data but it appears that 5G radiation has an impact on skin temperature, oxidative stress which also can also negatively impact the immune system.

- Why has it become so difficult for independent scientists to announce and share their opinion? What do you think about some of the concern of increasing Censorship matters of Science on Social media and in scientific journals (publications)?

- It is very irritating that some renowned scientist being censored and ridiculed on social media platforms or even getting removed from their jobs for speaking out their opinion. I personally use mainly LinkedIn, since I found it to be a good place to interact and discuss science with experts around the world but even there a lot of my connection experience censorship of their posts or are shut down like Dr. Robert Malone how made the initial experiments with mRNA in 1989 and laid the fundaments for mRNA vaccines. Science lives from discussion and only progresses with discussion so different opinions are pivotal and have to be freely shared and discussed without being censored by an algorithm or social media platform. Even in the main scientific journals there seems to be a “consensus” which I know we don’t have.

- What do you think about the current mRNA vaccines?

- I’m a real fan of the mRNA technology since I follow that field for over 20 years now and am really proud of the two Germany companies BioNTech and CureVac and their achievements especially given the devastating founding landscape in Germany and the skepticism around RNA use for drug purposes, even further when one knows that Merck already owned a patent and decided to go with DNA . Further, the groundbreaking work by your fellow countryman Katalin Kariko and her findings how to stabilize RNA and hide it from the immune systems danger receptors paved the ground for the mRNA vaccines and form my perspective the technology evolved and matured within the 3 decades of research and I’m so convinced of this technology that I also chose to get the BioNTech vaccine. With respect to the strategy applies what I said earlier I wished for more antigens and that it can be done is demonstrated, i.e., BioNTech’s BNT111 that delivers 4 antigens plus as discussed previously a nasal application, maybe oral will as well. By the way, I read reports that people are scared by the modified RNA nucleotide but would take Remdesivir without reservation. This seems a bit odd when you know it consists as well of a modified nucleotide but in a much higher concentration.

[10] https://www.heidi.news/explorations/arn-messager-la-revanche-des-outsiders/arn-ou-adn-a-une-lettre-pres-merck-decrochait-la-timbale

- How microthrombosis formation of the blood circulation can be overcome? There is evidence that mRNA vaccines have this effect and are not given to airplane pilots on long-haul flights.

- I haven’t heard of these airplane pilots, did not find any article or warning by any government or flight agency. What is reported about were the cases with vaccine-induced immune thrombocytopenia (VITT) that were observed in rare cases (5 per million) and are similar in etiology to heparin-induced thrombocytopaenia (HIT) with pre-existing plate factor 4 (PF-4) antibodies for which multiple test exist. There seems to be also a risk for mRNA vaccinees but to an even lesser extent .

[11] https://www.heidi.news/explorations/arn-messager-la-revanche-des-outsiders/arn-ou-adn-a-une-lettre-pres-merck-decrochait-la-timbale

[12] https://www.mdpi.com/1420-3049/26/16/5004