Dr Robert Hess: Differing opinions about the Lambda variant: Super mutant, successor to Delta or damp squib?

Dr Robert Hess takes 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.

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 severity), 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.

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.

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.

As experts in the field of human and molecular genetics and thus also on the topic of mutations, Dr Robert Hess provides 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.

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.

Doctor Robert Hess comments about recent studies that 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 Salvagene 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.

For the first time since the Salvagene SARS-CoV-2 Task Force was established 18 months ago, a difference of opinion has arisen, specifically with regard to the Lambda variant. What everyone agrees on is that the Lambda or C.37 variant is clearly more contagious than the original Wuhan strain. In addition, it is much more resistant to antibodies, and the existing vaccines therefore have a reduced efficacy against it. The reason for this is three mutations in the spike protein, which render it less susceptible to neutralization by antibodies. Added to which there are two mutations that make the variant itself more infectious.

...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”).

Dr Robert Hess skepticism regarding the efficacy of all previous vaccines against the Delta variant has been confirmed by the announcement from BioNTech/Pfizer that they are working on a vaccine that will specifically target this mutant. So far, we have been testing only one of the two immunity pillars, namely antibody production. In addition to checking the full range of antibodies, we at Salvagene go far beyond the generally applied classification to differentiate between the neutralizing antibodies and identify efficacy classes – low, medium and high – plus ADE antibodies which may even have the undesired effect of amplifying an infection. From now on, we will also be measuring the second Covid-19 immune pillar – namely T cell immunity – in great detail. For this purpose, we have upgraded our Covid-19 Immunization Program with the inclusion of the new SARS-CoV-2 T-Cell immunity analysis.