2019 - A Year of Viruses in Review

This year was full of fascinating discoveries. New viruses were identified, and others were associated with new and old diseases. Milestones were reached in the battle against viral diseases, and yet viral outbreaks continued to frighten the world. Scientists uncovered novel technologies to diagnose viral infections, and to deliver gene therapies that achieved results we could not imagine decades ago. Virologists learned more about the role the human microbiome plays in viral infection. This is the year in review with the findings that shaped 2019 in the field of viruses.

New diseases and viruses

A new polio-like disease outbreak (acute flaccid myelitis, or “AFM”) emerged in the United States in the last years, with more than 500 cases reported by CDC. AFM brought us back memories and fears from the early 1940s in the US, where after a few years of small polio outbreaks in American children, many more episodes would come in the following years paralyzing more than 50,000 children at the peak of the1952 epidemic. In 2019, epidemiological and immunological studies associated the new polio-like disease with other picornaviruses, enterovirus D68 and A71.

Human herpesviruses 6 (HHV-6) and Epstein-Barr virus (EBV) were associated with multiple sclerosis in humans. HHV-6 and HHV-7 were also linked to Alzheimer’s disease. Adenovirus C was associated with type I diabetes, and human papillomavirus infection correlated with increased odds of breast carcinoma.

An entire new family of viruses, the redondoviridae, was found in the human lung during metagenomic analyses. The “medusavirus”, was identified in a hot spring in Japan. The medusavirus infects amoeba cells and its genome is among the largest and more complexed viral genomes ever found, with genes encoding all types of histones.

Scientists demonstrated for the first time that a non-enveloped insect RNA virus, “Providence virus”, can also infect plants and mammalian cells, suggesting that plants could act as reservoirs of human viruses. Another study reported that more viruses than previously elucidated (about 30 different viral species) can be found in human semen.  The list included viruses of known routes of sexual transmission, such as HIV or HTLV-1, and also others like Lassa, Zika or Dengue. Proof of sexual transmission of dengue virus was confirmed in 2019 for the first time.

New viral therapies

This was not a great year for FDA approvals for antiviral therapies. 54 new drugs were approved by the FDA in 2019, included 48 new small-molecules. None of them target viral diseases. Xofluza (baloxavir marboxil), an inhibitor of the influenza virus polymerase acidic endonuclease, was approved in October 2018 for the treatment of acute uncomplicated influenza, in healthy people 12 years and older. In October 2019 Xofluza was also approved for the treatment of people at high risk of influenza complications, including those with asthma, chronic lung disease, diabetes, heart disease and obesity. During 2019 we heard great news about the first anti-influenza drug approved in more than 20 years. Therapy with Xofluza was found useful at preventing flu transmission in the household environment, reducing the chances of transmission in individuals under the same house by over 85%. However, in November, results from a study reported alarming rates of baloxavir-resistant strains, especially in children. The appearance of drug-resistance is common among RNA viruses, but the study found the troublesome ability of the virus to mutate without compromising its "viral fitness". Some scientists questioned the use of the antiviral in children, where resistant rates were significantly higher.  

In October, Descovy (Gilead), a combination of emtricitabine and tenofovir alafenamide, became the second therapy ever to be approved for HIV pre-exposure prophylaxis (PrEP). The new pill demonstrated efficacy similar to Truvada (also by Gilead), but with significantly less side effects. 

In December, the FDA rejected an application by ViiV, of what could have been the first long-acting HIV treatment. The new therapy, meant to be dosed in a monthly injection, combines the integrase inhibitor cabotegravir with the NNRTI rilpivirine. The FDA mentioned chemistry’s manufacturing and control processes as the reason for the rejection, but no concerns about adverse side effects were cited.

The final results of the clinical trial “PALM” in Africa brought us some of the best news of the year. Two antibody therapies for Ebola virus disease (EVD) were successfully tested. The single monoclonal antibody MAb114 (Ridgeback Biotherapeutics), and the combination of three antibodies in REGN-EB3 (Regeneron), reduced the number of deaths in EVD patients by two thirds overall. When patients were treated early after the presence of symptoms, deaths were reduced by near 90%. For the first time since the discovery of the Ebola virus in 1976, the disease was no longer a death sentence. 

Promising results of other novel drugs under development  were also presented in 2019, included the first-in-class HIV capsid inhibitor GS-6207 (Gilead), with potential to be dosed every 6 months, and the experimental CMV inhibitor maribavir, which showed superiority over Roche’s valcyte in a phase II trial.

 New Vaccines

Several vaccines were approved in 2019, and other experimental vaccines under development achieved important milestones. Work continued in the development of a universal influenza vaccine, and efforts were maintained on the search for an effective vaccine against HIV.  

Among the major stories of 2019 was the approval of Merck’s Ebola vaccine (Ervebo) by the European Medicines Agency in November, and by the US FDA in December. Since 2014, more than 28,000 cases of EVD, and over 11,000 deaths, have occurred in Africa. The vaccine was approved after a titanic trial performed in Africa tested a “ring” strategy with 236,000 individuals. The vaccine’s trial demonstrated 100% efficacy at preventing transmission of Ebola to individuals who have had close contact with infected individuals. Another Ebola vaccine manufactured by Johnson & Johnson, was also tested during 2019 in DR Congo, where the second largest outbreak of Ebola has been active since August 2018. Both vaccines utilize viral vectors expressing Ebola antigens to elicit immune responses. Importantly, both Ebola vaccines use non-pathogenic viral vectors and cannot induce EVD.

Takeda’s experimental Dengue vaccine (TAK-003) was also tested in 2019. The vaccine was 80% effective in a massive phase 3 study involving more than 20,000 individuals. Expecting approval in 2020, the drug-maker opened soon after a vaccine manufacturing plant in Germany. A single-shot vaccine against Chikungunya virus (another flavivirus) also demonstrated durable protection against the virus.

In September, before the onset of the 2019-2020 influenza season in the northern hemisphere, scientists reported that the flu vaccine will likely be suboptimal, due to strain mismatches with the prevalent viruses observed at the end of the Southern hemisphere season.

In the HIV arena, several vaccines were tested. The trial “HVTN-105”, evaluated several antigen combinations in humans, demonstrating neutralization antibodies in as little as 6 weeks. Several animal model studies showed promising proof-of-concept results, including an approach aimed at inducing broadly-neutralizing antibodies against HIV by using serial immunizations to prime the immune system. Follow up studies with this and other HIV vaccines are expected in humans, perhaps in 2020.

On the not-so-positive side, this year we found that the administration of the type 2 polio attenuated vaccine (still in use in developing countries) was halting eradication of the disease. More polio cases are now caused by the vaccine than by the wild virus. The situation is so extreme that watershed in some areas of the Philippines are contaminated with the polio vaccine-derived virus.

The dramatic consequences of under-vaccinating the population against viral diseases was a common topic in the news. Measles immunization rates plummeted in 2019, and outbreaks reached unprecedented numbers. The CDC reported near 1,300 cases in the US, the highest since 1992. Worldwide, W.H.O estimated more than 413,000 cases, with Central Africa taking the highest toll with more than 250,000 cases in DR Congo. Compounding the problem of measles under-immunization, researchers reported the presence of “immune amnesia” in children infected with measles. Two publications found that measles infection diminishes the levels of pre-existing antibodies against other pathogens like flu or pneumonia. Children recover from measles, but they become more vulnerable to other infectious diseases.

The microbiome

In 2019 scientists reported more evidence linking human microbiota with responses to viral infections. Some of the most striking effects were seen with rotaviruses, which cause millions of cases of diarrhea and estimated 200,000 deaths yearly. Researchers found that specific bacteria in the gut can protect, and also cure, rotavirus infection in mice. The effects of the bacteria can be transferred by fecal transplant to other mice, which then become resistant to rotavirus infection. Studies with mice also found that gut microbes can protect against neurologic damage from other viral infections.

Even more surprising was the effect of the microbiota on the response to vaccines. Trials with non-human primates showed that rectal microbes could influence the response to an HIV vaccine. The levels of lactobacillus and clostridia in the rectum of the animals improved the response to the vaccine, which was given through the skin. Similar results in other animal models were observed with other vaccines, including influenza and polio vaccines. Other findings highlighted a negative role for antibiotics during vaccination and viral infection. Administration of antibiotics to mice made them three times more susceptible to succumb after a deadly exposure to influenza virus. Studies in humans are still in their infancy, however, the findings in animal models highlight the need to elucidate whether the microbiota in some tissues may modulate the response to viral infection in other areas of the human body

Bacteriophages

The year also brought exciting news about the human virome, and especially bacteriophages. Previously, scientists have discovered unexpected links of the microbiota with many pathological conditions such as cancer, autoimmunity, viral infections, and mood disorders among others. Now, the use of phages as precise biological weapons to eliminate “unwanted” bacteria has made a medical comeback. Examples have appeared for the use of phages to treat deadly infections with antibiotic-resistant bacteria. However, the therapeutic use of phages has expanded to unexpected areas. In November, researchers at UCSD and collaborators, applied for the first time phage therapy to cure mice affected by alcoholic liver disease. Scientists first linked the toxin of a specific bacteria (enterococcus faecalis) with medical complications present in human patients with alcoholic liver disease. E. faecalis thrives in the gut of individuals with the disease, and transferring the bacteria to mice resulted in alcohol-induced liver disease in the animals. After screening thousands of phages, one virus was identified that killed enterococcus faecalis and cured the disease in mice.

Scientists also found that the human gut virome, mostly formed by bacteriophages, is more person-specific and stable over time than previously thought. The findings contrast with the human microbiome, where there are more members shared among individuals.

Viral-based gene therapies

2019 was the year of the revival of gene therapy. Twenty years after the death of Jesse Gelsinger, who died after the administration of an adenovirus vector, gene therapy trials took off again and brought us some of the most exciting results. Superior, more stable, efficient, and less immunogenic versions of different viral vectors played a pivotal role in the advancement in this field. Adeno-associated viral (AAV) vectors, and lentiviral vectors derived from HIV, dominated the field. This December, an update from the phase 1/2 trial in humans sponsored by Bluebird Bio, demonstrated spectacular cures for the treatment of sickle cell anemia. The approach uses a lentiviral vector to deliver a beta globin gene into the same patient’s stem cells. On average, the transduced gene was expressed in 40% of the patients’ blood cells. The therapy stopped the painful episodes of the disease and relieved near 80% of patients from the need for therapeutic blood transfusions.

Surprising results were also observed earlier in April, when another trial using allogeneic hematopoietic transplantation of cells transduced with a lentiviral vector, were used to cure children afflicted with a severe immunodeficiency (SCID-X1).

Trials using AAV vectors also made it to the news, including those testing Novartis therapy (Zolgensma) for spinal muscular atrophy (SMA), which was approved this May by the FDA. Zolgensma is the second gene therapy ever to hit the market. The therapy became the most expensive single-dose treatment in history, at a cost of $2.1 million per patient. Other AAV-based experimental therapies were tested in animal models with promising results, including a treatment for epilepsy, a therapy for Duchenne muscular dystrophy, and a new approach for amyotrophic lateral sclerosis (ALS).

Not surprisingly, FDA commissioner Scott Gottlieb, announced earlier in January that by 2020 the institution expected to receive more than 200 INDs per year for cell and gene therapies, and by 2025 the FDA anticipates approval of 10 to 20 of these products every year.

Typically, the scope of gene therapy treatments has covered serious immunological disorders, neurodegenerative diseases, or deadly cancers like lymphomas. However, in November Harvard scientists and Rejuvenate Bio, tested AAV-based therapies in mice models. They were able to successfully increase the health and life-span of mice using murine models for obesity, heart failure, and type 2 diabetes. A few weeks later, another company, Libella Gene Therapeutics, indicated its intentions to initiate the first ever trial aimed at reversing the biological age of humans. Libella’s therapy will use AAV vectors delivering human telomerase.

And much more…

Other fascinating milestones in 2019 included the use of CRISPR technology to combat viral infections. Scientists used it to eradicate latent infections of herpesvirus in tissue culture. CRISPR was also successfully tested to eradicate in human cells infections with Ebola, Zika and influenza virus, and also to cure living animals (mice) infected with HIV. Chinese scientists also tried to cure HIV in humans using CRISPR, but the attempt was unsuccessful.

In 2019 we were able to see for the first time the video of a virus assembling in real time. Researchers studying an endogenous retrovirus decimating the wild population of Koalas, described for the first time the existence of an “immune system” for the genome. An RNA-based machinery was found to protect the genome against challenges by new intruder retroviral elements. Other researchers exploited the use the reactivation of some endogenous retroviruses in transformed cells to combat cancer. Scientists identified first retrovirus specific self-antigens in cancerous cells, and then explored the use of therapeutic vaccines to target these antigens.

Virologists also discovered that the miracle drugs that cure hepatitis C infection at high rates, yet, they fail to erase an epigenetic mark originated by the virus. This genetic signature persists in the patient’s cells even when the virus has been eradicated. Scientists believe this could explain why in some cases the oncogenesis process initiated by HCV infection continues even after the virus is no longer there.

With another year ending, we should take a moment to appreciate the efforts of thousands of scientists, physicians, epidemiologists, and clinicians working in pharmaceutical and biotechnology companies, in CROs and hospitals, who made these new therapies a reality. We should be grateful to the thousands of patients who volunteered for the testing of antivirals and vaccines. And lastly, to the many researchers who first came with the discovery, the proof-of-concept, or just the idea, who translated into new therapies. Researchers who will surprise us again in the coming years with amazing discoveries and advances that will escape our imagination.

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