Virus World

Remdesivir sped recovery of patients by several days, although it’s “not a home run. A candidate treatment for COVID-19 has shown convincing—albeit modest—benefit for the first time in a large, carefully controlled clinical trial in hospitalized patients. The infected people who received remdesivir, an experimental drug made by Gilead Sciences that cripples an enzyme several viruses use to copy their RNA, recovered in an average of 11 days versus 15 in patients who received a placebo. “Although a 31% improvement doesn’t seem like a knockout, 100% [success], it is a very important proof of concept,” said Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID), during an Oval Office meeting in which President Donald Trump was asked by media about a statement Gilead had released on the results. The patients treated with remdesivir also had a lower mortality rate—8% versus 11.6% in the group given the placebo—but this positive trend did not reach statistical significance, Fauci noted. (The full results from the trial have not been made public in a preprint or peer-reviewed paper.)

NIAID sponsored the study, which began on 21 February and enrolled 1063 patients at 68 sites in the United States, Europe, and Asia. A board that monitors safety and data from the trial informed investigators on 27 April that remdesivir was better than the placebo. Fauci says the board is releasing the overall results early in part on ethical grounds: Given the positive data, remdesivir must now be offered to all study participants, and trials of other treatments now underway must start to offer the drug instead of a placebo, Fauci said. The search for COVID-19 treatments that can do better than remdesivir remains a top priority. “It’s a promising signal, but we do not need to get hyperexcited—this is not a home run,” says Carlos del Rio, an infectious disease clinician at Emory University, one of the larger sites that participated in the remdesivir trial. In essence, he says, the study showed that patients who received the drug, which is given intravenously, could stop receiving supplemental oxygen earlier. Del Rio, a veteran of HIV drug development, which gradually advanced from nothing to effective treatments, hopes the results mark a first step for COVID-19. But he does not expect remdesivir will significantly ease the demands that COVID-19 is putting on hospitals, or brighten prospects for lifting shelter-in-place orders...

One of the nation's top health experts recommends continuing avoiding large crowds and social interactions as the best defense against the pandemic.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has initiated the Collaborative Influenza Vaccine Innovation Centers (CIVICs) program, a new network of research centers that will work together in a coordinated, multidisciplinary effort to develop more durable, broadly protective and longer-lasting influenza vaccines. NIAID will provide up to approximately $51 million in total first-year funding for the program, which is designed to support the CIVICs program centers over seven years.

“To more effectively fight influenza on a global scale, we need better influenza vaccines that are more broadly protective,” said NIAID Director Anthony S. Fauci, M.D. “With the CIVICs program we hope to encourage an exchange of ideas, technology and scientific results across multiple institutions to facilitate a more efficient and coordinated approach to novel influenza vaccine development.” Seasonal influenza causes hundreds of thousands of hospitalizations and tens of thousands of deaths in the United States each year, according to the Centers for Disease Control and Prevention. While current seasonal influenza vaccines are widely available and provide important public health benefit, they could be improved. Notably, they do not always protect against all strains of circulating influenza viruses. Each year, months ahead of the flu season, scientists must make their best prediction as to which circulating viruses will be dominant. New seasonal influenza vaccines must be manufactured, distributed and administered to keep up with constantly evolving influenza viruses. This process can be slow, and if a drifted seasonal influenza virus emerges, that can impact the effectiveness of the vaccine against that virus. The relatively long timeline for vaccine production and the rapidly changing nature of influenza viruses poses a unique and difficult public health challenge for these reasons.

The CIVICs network will develop so-called universal influenza vaccines, which could provide longer-lasting protection than current vaccines and against a wider variety of influenza viruses. The CIVICs centers will conduct multidisciplinary research that supports the development of vaccine candidates through testing in preclinical studies, clinical trials and human challenge studies. The CIVICs network also will explore approaches to improve seasonal influenza vaccines, such as by testing alternative vaccine platforms or incorporating new adjuvants (substances added to vaccines to boost immunity). These advances could substantially reduce influenza hospitalizations and deaths in the future.

The CIVICs program will include three Vaccine Centers, one Vaccine Manufacturing and Toxicology Core, two Clinical Cores, and one Statistical, Data Management, and Coordination Center (SDMCC).

The Vaccine Centers will focus on designing novel vaccine candidates and delivery platforms with an emphasis on cross-protective vaccine strategies that could be used in healthy adults as well as populations at high risk for the most serious outcomes of influenza, such as children, older adults, and pregnant women. The Vaccine Centers also will focus on new ways to study influenza viruses and the human immune response to them through computer modeling, animal models and human challenge trials. The most promising candidate vaccines will advance to clinical trials conducted by the Clinical Cores. Vaccine candidates will first be evaluated for safety and immunogenicity in small Phase 1 clinical trials conducted among healthy adult participants. Successful vaccine candidates may eventually be advanced to larger Phase 2 clinical trials in healthy adults, or in specific age groups or at-risk populations. The Vaccine Manufacturing and Toxicology Core will work with the Vaccine Centers to develop and manufacture the vaccine candidates for clinical testing.....

Hospitalized patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to a preliminary data analysis from a randomized, controlled trial involving 1063 patients, which began on February 21. An independent data and safety monitoring board (DSMB) overseeing the trial met on April 27 to review data and shared their interim analysis with the study team. Based upon their review of the data, they noted that remdesivir was better than placebo from the perspective of the primary endpoint, time to recovery, a metric often used in influenza trials. Recovery in this study was defined as being well enough for hospital discharge or returning to normal activity level. 

Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059). More detailed information about the trial results, including more comprehensive data, will be available in a forthcoming report. As part of the U.S. Food and Drug Administration’s commitment to expediting the development and availability of potential COVID-19 treatments, the agency has been engaged in sustained and ongoing discussions with Gilead Sciences regarding making remdesivir available to patients as quickly as possible, as appropriate. The trial closed to new enrollments on April 19. NIAID will also provide an update on the plans for the ACTT trial moving forward. This trial was an adaptive trial designed to incorporate additional investigative treatments.         

A trial in South Africa was halted after early analysis found no protection.  The failure-ridden search for a vaccine that can stop the AIDS virus has delivered yet another frustrating defeat. The HIV vaccine that had moved furthest along in human testing does not work, and the $104 million trial in South Africa evaluating it has been stopped early. “There’s absolutely no evidence of efficacy,” says Glenda Gray, who heads the study and is president of the South African Medical Research Council (MRC). “Years of work went into this. It’s a huge disappointment.”

The efficacy study, which began in October 2016, is known as HVTN 702. It enrolled 5407 sexually active, HIV-uninfected men and women between 18 and 35 years of age at 14 sites across the country. Researchers randomly assigned half of the participants to receive a pair of HIV vaccines used in a one-two punch called a prime boost, whereas the other half received placebo shots. The trial was supposed to last until July 2022. But on 23 January, an independent monitoring board that takes scheduled, sneak peaks at the data to evaluate safety and efficacy, informed Gray and the other leaders of the study that it was “futile” to continue. There were 129 infections in the vaccinated group and 123 in those who received the placebo. “I was catatonic,” Gray says. No evidence exists that the vaccine caused harm, as happened in a different large HIV vaccine study that was abruptly halted in 2007. Susan Buchbinder, an epidemiologist at the University of California, San Francisco, who co-chaired that earlier sobering study, congratulates her colleagues in South Africa for conducting a scientifically rigorous, complex trial. “The trial was incredibly well done and we got a definitive answer, and that’s what science is about,” says Buchbinder, who is the chair of a multicountry trial, Mosaico, that now is the most advanced large-scale HIV vaccine study underway.

In the halted trial, funded by MRC, the U.S. National Institute of Allergy and Infectious Diseases (NIAID), and the Bill & Melinda Gates Foundation, the “prime” was a harmless canarypox virus that carries genes for HIV’s surface protein and two of its other structural proteins. The boost contained a recombinant version of the surface protein mixed with an immune system booster, or adjuvant, called MF59. Many HIV scientists had doubted the South Africa study would succeed because the vaccines used in the prime-boost scheme had only produced lackluster results in an efficacy study in Thailand. In that study, which ended in 2009, HIV infections totaled 51 in the vaccine group and 74 in the placebo arm—an efficacy of 31%. The field widely agreed that this wasn’t a high enough level of protection to bring the vaccine to market, but researchers were divided as to whether it made sense to try to build on the vaccine or abandon it.....

A novel experimental vaccine against respiratory syncytial virus (RSV), a leading cause of severe respiratory illness in the very young and the old, has shown early promise in a Phase 1 clinical trial. The candidate, DS-Cav1, was engineered and developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, who were guided by their atomic-level understanding of the shape of an RSV protein. An interim analysis of study data showed that one dose of the investigational vaccine prompted large increases in RSV-neutralizing antibodies that were sustained for several months. 

First described in 1956 as a cause of infant pneumonia, the health burden of RSV has long been underappreciated. In fact, the virus is an important contributor to serious illness worldwide and causes as many as 118,000 deaths annually among young children. In the United States each year, RSV infections account for approximately 57,000 hospitalizations and 2 million outpatient clinic visits among children younger than five years old, according to the Centers for Disease Control and Prevention. 

“A vaccine to prevent RSV is a long-sought goal that has eluded us for decades,” said NIAID Director Anthony S. Fauci, M.D. “The early results of this trial suggest that this structure-based strategy for developing an RSV vaccine may bring that goal within reach.”  After four weeks, levels of RSV-neutralizing antibodies in those who received 50 µg of vaccine (with or without alum) had increased sevenfold over the levels present prior to vaccination. A single dose of 150 µg without alum boosted neutralizing antibody levels 12-fold, while alum-adjuvanted vaccine at that dose prompted a 15-fold surge in neutralizing antibodies. The vaccine-induced antibody levels greatly exceed those seen following natural RSV infection in human challenge trials (where healthy volunteers are exposed to pathogens under carefully controlled conditions in order to observe the course of infection), when neutralizing antibody levels merely triple over those present before infection.

Original findings were published in Science on 02 August 2019:

https://doi.org/10.1126/science.aav9033