1. Goodwin, Peter M.

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Patients with cancer as well as general populations could potentially achieve lifelong immunity to the novel coronavirus COVID-19 from a proposed oral vaccine delivering a live, attenuated ("castrated") virus that targets gut memory T cells and the gut microbiome, according to Miguel Bronchud, BA, MA, BM, BCh, MRCP, DM, PhD, DGHE, a cancer scientist and medical oncologist from the Department of Oncology at GenesisCare and Clinica Corachan in Barcelona. He is known for his early work on recombinant human G-CSF development (at the Christie Hospital in Manchester) and his more recent immunology work on the potential role of placental immune editing switches (PIES) in modulating immune surveillance and cancer progression in a variety of malignancies. Unfortunately, at the time of article publication in March, he was battling the coronavirus infection himself in isolation at his home (but gradually improving).

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Types of Vaccines

While the search for antiviral drugs continues, Bronchud was adamant that cancer doctors urgently needed a COVID-19 vaccine to protect their uniquely at-risk patients. Cancer patients and the general public needed a wider choice of candidate vaccines, and this should especially include orally administered live vaccines, which he concluded were likely to be the most effective.


"This [oral] vaccine is not the easiest way forward," he told Oncology Times, since it was "much easier" to develop a conventional SC or IM route vaccine. "But we all know from personal experience how poorly such conventional vaccines for influenza perform at times. And [to have] to repeat a COVID-19 vaccine every year-if needed-could be a true nightmare and a heavy burden financially," he noted.


Although promising research using dead vaccines is already urgently being undertaken in Madrid-on the closely related severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) viruses-and in the U.S., China, Germany, Israel, the U.K., and Australia, Bronchud is convinced that using SC or IM injections of dead virus was an insufficient solution.


"I don't think that's gonna be the definitive answer," he said, "because influenza viruses do that, and don't really work. [They] cause only short-term and partial protection. And every year there's a new epidemic."


Bronchud applauded the fast development and proposed fast pre-clinical and clinical testing of the "Oxford Vaccine" (announced recently by Adrian Hill of Oxford University's Nuffield Department of Medicine) and Cambridge University's proposal of the digitally designed Immune Optimised Selected and Synthesized Vaccines (DIOSynVax) approach that involves using computer modelling of the virus's structure, using information on the COVID-19 virus itself, as well as its relatives (SARS, MERS, and other coronaviruses), to identify parts of its armor-crucial pieces of the "spikes" that will form part of the vaccine to disable the virus but without making the infection worse.


In the current dramatic pandemic situation, Bronchud also defended "any other sound development of vaccines." He cited one from the U.S.-a vaccine candidate identified just 42 days after the novel coronavirus was sequenced. Researchers are working with the National Institutes of Health on a healthy-volunteer study that began early in March 2020. The product is a synthetic strand of messenger RNA (mRNA) designed to convince bodily cells to produce antibodies against the virus. "If mRNA-1273 proves itself to be safe, [researchers] will enroll hundreds more patients to determine whether the vaccine protects against infection," he said.


Bronchud was also pleased to see other diverse options being developed at present (by prestigious laboratories in Israel, Australia, Germany, and by some big pharmaceutical corporations) including the not yet fully published vaccine that is close to testing in a clinical trial in China. It involves taking a segment of the coronavirus genetic code and entwining it with a harmless virus, thereby exposing healthy volunteers to the novel infection and spurring the production of antibodies.


"We might still be in time to evaluate the oral live attenuated models-considering also that in several other animal species coronavirus infects primarily the small gut," said Bronchud. He noted the oral Sabin vaccine in the 1950s and 1960s brought inexpensive protection against polio to the masses in low- and middle-income countries, as well as to developed nations with the "little sugar vaccine"-widely and rapidly accepted by children worldwide and conferring life protection.


But he was also candid about the fact that not all attenuated viruses worked. He quoted the example of the attenuated virus samples that Albert Sabin used to create his oral polio vaccine (given to him by Hilary Koprowski) that had ultimately been unsuccessful. "And at present, we don't seem to have a perfect animal model of human COVID-19 infection-particularly [one that] reliably mimics the most vulnerable patient groups or-in younger [patients]-almost idiosyncratic exceptions," said Bronchud.


Also, an orally administered vaccine active primarily in the gut was able to target both humoral and cell-mediated immune responses, he said. And he pointed out that the role of the gut in COVID-19 infection might have been overlooked to some extent.


In the journal Gut, Weicheng Liang and his colleagues in China shared data showing that in a series of pneumonia cases caused by COVID-19 the most common symptoms in patients were fever and cough (2020; doi: 10.1136/gutjnl-2020-320832). But the incidence of leucopenia, fever, and diarrhea in the three studies showed a statistically significant difference, and diarrhea displayed the smallest "p-" (p=0.016). The investigators noted that clinicians may underestimate the value of this symptom in clinical practice, and that this may affect diagnostic accuracy.


Bronchud noted that recent studies showed that the "spike protein" of COVID-19 shared the same cell entry receptor angiotensin-converting enzyme 2 (ACE2) as the SARS virus, and that the pathological importance of ACE2 could be in modulating intestinal inflammation and diarrhea. (The Chinese researchers examined the expression profiles of ACE2 in various human tissues and found that ACE2 was highly expressed in the human small intestine.)


To start urgent work on the proposed live-attenuated oral vaccine for COVID-19, Bronchud urged teams to have access to top safety ("P4" security) laboratories (such as those available in the U.K. and the U.S.) to obtain enough COVID-19 attenuated viruses for clinical testing through in vitro culture of human cells infected with the main pathogenic COVID-19 strain. He proposed the harnessing of Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated system (CRISPR/Cas9) gene-editing technology be used to "castrate" the pathogenicity and enhance the immunogenicity of the virus by oral route.


Bronchud noted that CRISPR/Cas9 gene-editing had already dramatically reshaped the ability to edit genomes and that one of its most important uses was for developing potential therapeutic strategies against diseases. But it was equally suitable for castrating the COVID-19 virus and had already been used in the battle against diseases like cancer; genetic, immunological and neurological disorders; and viral diseases, he said.


Bronchud found it "very interesting" that in a recent publication from Zhang and his group in China the main protease of coronaviruses and the 3C protease of enteroviruses shared a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate (J Med Chem 2020; doi: 10.1021/acs.jmedchem).


Because of their "unique" specificity and essential role in viral polyprotein processing, these proteases were not only suitable targets for the development of antiviral drugs, said Bronchud, but perhaps also for the much-needed development of effective human coronavirus vaccines.


"The reports that COVID-19 has been found in human feces of symptomatic patients-if true-may suggest that (together with implications surrounding gut microbiome immunological function) it might be [a] possible and worthy [route] to try a human COVID-19 vaccine by oral route," he said.


Gastrointestinal tissues were at the core of the immune system, and the reticulo-endothelial systems were rich in memory T cells, Bronchud noted. The gut has recently become an active focus for cancer doctors in the setting of stem cell transplantation because of the discovery that microbiome diversity influences outcomes in hematologic malignancy.


Bronchud told Oncology Times that gut symptoms in COVID-19 infection had been detected in patients. "Many children and some adults here in Spain report early-almost prodromal-GI symptoms including nausea and diarrhea before respiratory symptoms, if any," he said. Symptomatic detection of the infection and potentially a key to long-lasting immunity could emerge by addressing gut involvement in COVID-19 infection.


(This article is based on an interview with Miguel Bronchud conducted a week into his illness with COVID-19 from his home in Barcelona.)


Peter M. Goodwin is a contributing writer.