Researchers all over the world are looking to new therapeutic options for treatment or prevention or the Covid-19 epidemic. Not only looking at human medicines: many activities are ongoing also in the veterinary sector, where a new guidance has been issued by the EU  Commission, EMA and the Coordination Group for Mutual Recognition and Decentralised Procedure – Veterinary (CMDv) to illustrate the possible flexibilities in the development, manufacturing and distribution of veterinary medicines during the emergency (see also the article in the Regulatory section of this newsletter to know what EMA is doing to facilitate pharmaceutical companies, as many indications are similar for the human and veterinary sector). We provide some news about recent advancements, both for medicinal products and vaccines.

Looking for genetic risk factors

Precision Life, a UK company specialised in the use of artificial intelligence (AI) to analyse patients’ genomic and clinical data, published on its website the results of a study on Covid-19 patients aimed to identify genes potentially related to the sepsis associated to the disease. The study was based on a combinatorial association approach to analyse a sepsis population derived from UK Biobank, and led to the identification of 70 sepsis risk-associated genes, potentially related to the mechanisms underlying sepsis pathogenesis in severe Covid-19.

Several possible targets for a future therapy have been also identified, including endothelial cell dysfunction, PI3K/mTOR pathway signaling, immune response regulation, aberrant GABA and neurogenic signaling. The study also looked for medicines that might be repurposed to meet these targets, ending up in 59 possible candidates against 13 different sepsis risk genes. The selected active chemical compounds are all included in the DrugBank or ChEMBL databases. 

India is working on repurposing 

The protocol to use lopinavir/ritonavir combination therapy amongst symptomatic acute Covid-19 patients is just one example of the work the Indian Council of Medical Research (ICMR) is doing to identify already approved medicines that may turn useful to fight the virus (see more on the Times of India). The lopinavir/ritonavir combination was initially authorised to treat HIV infections, and then also used during the SARS and MERS coronavirus epidemics. Also disulfiram was already used in these instances, as it can promote the immune response; the drug was originally developed to fight alcohol dependence through the production of nausea and other unpleasant symptoms in contact with the alcohol. Loperamide is under study in India to treat Covid-19’s diarrhoea symptomatic manifestations. Among other medicinal products under investigation are the anti-inflammatory against psoriasis itolizumab and the immunomodulator tocilizumab, this last being widely used during the emergency also in Western countries. Immunomodulation is also the target of mycobacterium-w, a drug to treat leprosy which already proved useful in severe blood infections. 

FDA approved remdesivir for emergency use

On May 1st, the US Food and Drug Administration (FDA) issued an Emergency Use Authorisation (EUA) relative to Gilead’s anti-HIV remdesivir, on the base of a study showing the drug could cut of 31% recovery times for Covid-19 patients compared to placebo (see more on FiercePharma). The authorisation states that “based on the totality of scientific evidence available to FDA, it is reasonable to believe that remdesivir may be effective in treating Covid-19” if used under the prescribed conditions, and that “there is no adequate, approved, and available alternative to the emergency use of remdesivir for the treatment of Covid-19”.

The terms of the EUA establish that the drug can be supplied only to authorised distributors or directly to a US government agency, can be administered by IV infusion to treat patients with severe disease (SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation) at dosing regimens detailed in the authorised Facts Sheets. A Fact Sheet for patients and parents/caregivers has been also issued by the FDA.

The Agency also approved under EUA the use of the anti-malaria drugs hydroxychloroquine and chloroquine. Some 30 million doses of hydroxychloroquine sulfate were donated to the U.S. Department of Health and Human Services (HHS) by Sandoz, plus another million doses of Resochin (medical grade chloroquine phosphate) donated by Bayer Pharmaceuticals. The FDA also released a note to warn against the possible severe side effects of hydroxychloroquine, and the need of medical supervision for its administration.

Hyperimmune plasma and LMW heparins

The plasma of people that won the Covid-19 infection is rich of gammaglobulins, and it may be administered to patients to sustain their immune response. This hypothesis has been supported by analysts, as reported by FiercePharma, and it is under testing in Italy after a first successful experimentation in the Mantua and Pavia hospitals. 

The Italian Medicines Agency AIFA also authorised the off-label use of low molecular weight heparins, for the prevention of venous thromboembolism in the first phase of the disease and for the control of the severe thromboembolitic phenomena resulting from the advanced, hyper-inflammation phase of Covid-19.

Dr. Anthony Fauci, the head of the medical task force supporting the Trump administration in dealing with the pandemic, during a recent hearing at the US Senate commented the possibility for children to be back to school saying that “the idea of having treatments available, or a vaccine, that facilitate the re-entry of students into the fall term would it be something a bridge a bit too far. The drug that has shown some degree of efficacy, was modest, and was into hospitalised patients. […] Probably, the thing that would be closest to utilisation would likely be passive transfer of convalescents’ serum”, referred to the possibility to make a preventive immunisation to increase the safety of the students (see the video of the hearing, from min 58.22)

The difficult search for a vaccine

Many are the candidate vaccines under development worldwide (see the official WHO list), and it is difficult to guess who will be the winner. During the hearing at the Senate, the same Dr Fauci remarked there are some points of consideration applicable to the development of all vaccines.

First of all – he said –, there is no guarantee that the vaccine is actually going to be effective. You can have everything you think that’s in place and you don’t induce this kind of immune response that turns out to be protective and durably protective. So, one of the big unknowns is will it be effective? Given the way the body responds to viruses of this type, I’m cautiously optimistic that we will with one of the candidates get an efficacy signal. The other thing that is unknown, that’s of concern, but we will be able to go around this doing the testing properly, is that you do getting an enhancement. Namely, there were a number of vaccines, two in particular. […] The vaccines induce a sub-optimal response, and when the person gets exposed, they actually have an enhanced pathogenesis of the disease, which is always worrisome. So we want to make sure that that doesn’t happen. Those are the two major unknowns. Putting these two things together, we are cautiously optimistic that we will have a candidate that will have some degree of efficacy, hopefully, a percentage enough that will induce the kind of herd immunity that would give protection to the population at home.”  (see the video from min. 1.26.36)

The World Health Organisation released at the end of April a guidance document on the prioritisation of vaccines, stating that “should a vaccine’s profile be sufficiently superior to the critical characteristics under one or more categories, this may outweigh failure to meet another specific critical characteristic”. The WHO also advised companies working to the task that vaccines which would not meet multiple critical characteristics under the proposed criteria are unlikely to pass the assessment process. The criteria address candidate vaccines under different perspectives, assigning a certain amount of points to each item in order to obtain a prioritisation list. For each attribute it is provided the minimal acceptable profile to be met and the criteria to be used for assessment.

Many techniques under evaluation

The complexity and difficulties to be faced to obtain a truly useful and safe vaccine have been discussed by Derek Lowe in a commentary published in Science Translational Medicine. The problem is being addresses using many different techniques for vaccine development, some quite old and well established, other very new and still characterised by many question marks.

A starting point to take into consideration is that the Sars-Cov-2 appears to be a rapidly mutating virus (see for example here and here), thus making more difficult the availability of a truly efficient vaccine; this is similar to what already occurs with the influenza vaccine, for example, with the circulating wild type virus often different from strains used to manufacture the seasonal shots. 

Live attenuated virusvaccines are viral particles that cause a real, but attenuated infection. This category is often the most efficient in generating a long-lasting immunity. According to Derek Lowe, the difficulty is represented by the fine tuning necessary not to generate a virus too “aggressive”, thus leading to the true disease, obtained by a lab process imitating the natural mutation that occurs during time upon co-existence of the virus and the human host. 

“Inactivated virus” vaccines utilise completely unfunctional virus obtained by exposition to high temperature or desaturating agents, i.e.formalin or beta-propiolactone. The immunisation procedure requires booster shots, as the efficiency of the vaccine is lower; reproducible manufacturing can also represent a challenge to be achieved. 

Some vaccines are based just on one protein or piece of protein of the virus, able to cause the immune response in the host. This make them easier to manufacture, since it is possible to use recombinant technology, but they often require the use of adjuvants to produce a sufficient immune response. Recombinant proteins can also be assembled to give a “virus-like particle”(VLP) to be used as vaccine. 

DNA vaccines are quite young, based on circular plasmids coding for the antigen protein. The technique is similar to those used in gene therapy: upon insertion in the host cells using viral vectors, the target protein is hereby directly produced. The advantage is that the final product presents less issues with protein folding or glyco-post-modifications. No human product of this type is yet available; they would suffer the same problem of stability of gene therapies, suggest Derek Lowe. 

mRNA vaccines are also a recent category, using messenger RNA instead of DNA. Here the issue is represented by the need to limit the innate immune response against the infection in favour of the adaptive one generating antibodies against the target protein. Should this not occur, the immunity would be just short term. An advantage is a reduced immune response against the vector, but again there is a problem of stability of the mRNA.

Derek Lowe also discusses the different adjuvant technologies, and the many open questions as for the need to cope the demonstration of efficacy with the very tight timelines to reach the approval of the first vaccines to be use in humans. Shortcuts are inevitable, he argues; for example the animal testing of the Moderna’s mRNA vaccine has been completely skipped. The definitions of the endpoints – surrogate or not – for clinical studies is another open issue, as it is the length of the immunity provided both from the human disease and candidate vaccines. “My guess is that we may end up with a first-round vaccine that doesn’t last as long as it might, but will provide enough immunity to do the job and provide cover for us to collect more data on an optimised candidate”, writes Lowe.

Last, but not least, the question of safety is not secondary, as severe adverse effects might occur upon administration of medicines – as also vaccines are – targeting the immune system. “But you can’t avoid the problem: the huge person-to-person variation in everyone’s immune system means that these severe events can never be ruled out at some low level if you’re dosing enough people”, he adds.


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