Virus World

Filoviruses frequently emerge to cause terrifying outbreaks of often-fatal human disease. Treatment options so far have focused on monoclonal antibodies. Remdesivir is an adenosine analog that binds viral RNA polymerase to block replication by premature termination of RNA transcription. The drug has been successfully used intravenously for treating progressive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in humans. Cross et al. tested a related oral prodrug, obeldesivir (currently in phase 3 clinical trials for COVID-19 treatment), in nonhuman primates for its therapeutic value against filoviruses (see the Perspective by Sprecher and Van Herp). When administered to the animals within 24 hours of virus exposure once daily for 10 days, the drug conferred complete protection against lethal infection with Sudan ebolavirus. Having an oral drug would be a major logistical advantage for use in the remote, resource-poor areas where filoviruses occur. —Caroline Ash

Published in Science (March 15, 2024):

https://doi.org/10.1126/science.adk6176 

Primate centers band together for study rejected by Operation Warp Speed. Primate researchers in the United States have banded together in a push for an ambitious monkey study that would do head-to-head comparisons of the leading COVID-19 vaccine candidates. Although 10 candidates are already undergoing large-scale tests in people, proponents of the monkey plan say those clinical trials may not deliver the comprehensive data needed to choose the safest and most effective vaccines. The comparison trial in monkeys, in contrast, could shed light in a matter of weeks on how the candidates stack up on measures including potential side effects, the strength of immune responses they trigger, and how well they protect against infection and disease. “We should take a cold, hard look at all of the data and ask ourselves, ‘What appears to work best?’” says Nancy Haigwood, who directs the Oregon National Primate Research Center and is a key advocate for the comparative monkey study.

The proposed monkey vaccine comparison faces hurdles: It would add to the pressure on the dwindling U.S. supply of research monkeys, potentially delaying research on other diseases, and it does not yet have funding. Haigwood says she expected the U.S. government would gladly support the effort, which would cost an estimated $10 million, compared with the $10 billion the Trump administration’s Operation Warp Speed has already devoted to a COVID-19 vaccine push. But facing a lack of interest by current Warp Speed officials, Haigwood and colleagues at the six other national primate research centers are now turning to the National Institutes of Health (NIH) for support. Most developers of the vaccine candidates in efficacy trials have already published how well each works in monkeys against a “challenge” with SARS-CoV-2—a deliberate exposure to the pandemic coronavirus that causes COVID-19. But the details of how the experiments were conducted and the ways the results were analyzed differ so profoundly that immunologist John Moore of Weill Cornell Medicine says he can’t make sense of how the candidates compare. “It’s comparing apples to oranges and bananas,” says Moore, who has co-authored a review, on preprint.org, that compares the various monkey studies. 

The human vaccine trials, for their part, are likely to yield only preliminary signals of efficacy over the next few months, not clear-cut evidence that one or more is safe and protects people. “We’re going to get data dribbling in from clinical trials,” says Haigwood, a veteran AIDS vaccine researcher. The data from the many human trials, some in multiple countries, will also be tough to compare. Jay Rappaport, who heads the Tulane National Primate Research Center, notes the trial populations differ and are infected by different variants of SARS-CoV-2. In addition, the human trials—as with the monkey experiments—often use different assays to measure immune responses. “There’s so much variation in the primate studies, but there’s even more variation in the human studies,” Rappaport says. In contrast to the human trials that must wait for enough participants to become naturally infected to gauge a vaccine’s worth, Haigwood says, monkey challenge studies could deliver definitive results quickly. She says the monkey comparison could start as soon as this month and would require only about 6 weeks to vaccinate animals, challenge them, and assess their immune responses and levels of protection...

A single dose of an antibody-based treatment can prevent HIV transmission from mother to baby, new nonhuman primate research suggests for the first time. When that single dose is given is key, however. The study found rhesus macaque newborns did not develop the monkey form of HIV, called SHIV, when they received a combination of two antibodies 30 hours after being exposed to the virus.

Delaying treatment until 48 hours, on the other hand, resulted in half of the baby macaques developing SHIV when they were given four smaller doses of the same antibody cocktail. In comparison, the study found macaques that received the current standard HIV treatment – antiretroviral drugs – remained SHIV-free when they started a three-week regimen of that therapy 48 hours after exposure. “These promising findings could mean babies born to HIV-positive mothers can still beat HIV with less treatment,” said the study’s corresponding’s author, Nancy Haigwood, Ph.D., a professor of pathobiology and immunology in the Oregon Health & Science University School of Medicine, as well as the director at the Oregon National Primate Research Center at OHSU.

This is the first time a single dose of broadly neutralizing antibodies given after viral exposure has been found to prevent SHIV infection in nonhuman primate newborns. Previous research by Haigwood, Ann Hessell, Ph.D., and others showed four doses of antibodies started 24 hours after exposure prevented SHIV infection, with all 10 of the baby primates in that study not having any SHIV virus for six months. Both studies used a combination of two antibodies called PGT121 and VRC07-523. The new study also suggests a much shorter course of antiretroviral therapy given after virus exposure could prevent HIV transmission to newborns. Human babies born from HIV-positive mothers typically take the drug cocktail – a personalized regimen of multiple drugs taken daily – for about six weeks before being re-tested. If the tests are then positive, they likely need to take HIV drugs for the rest of their lives. But this study showed nonhuman primate newborns didn’t have SHIV after undergoing antiretroviral therapy for just three weeks starting 48 hours after exposure.

Published in Nature Communications (07 January 2020):

https://doi.org/10.1038/s41467-019-13972-y

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing antibody titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron. Significant and equivalent control of virus replication in lower airways was observed following either boost. Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.

Preprint available in bioRxix (Feb.04, 2022):

https://doi.org/10.1101/2022.02.03.479037 

NIH-led study of mRNA vaccine supports advance to Phase 3 human trials. Two doses of an experimental vaccine to prevent coronavirus disease 2019 (COVID-19)  induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2, report scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.  SARS-CoV-2 is the virus that causes COVID-19. The candidate vaccine, mRNA-1273, was co-developed by scientists at the NIAID Vaccine Research Center and at Moderna, Inc., Cambridge, Massachusetts. The animal study results published online today in the New England Journal of Medicine complement recently reported interim results from an NIAID-sponsored Phase 1 clinical trial of mRNA-1273. The candidate mRNA-1273 vaccine is manufactured by Moderna.

In this study, three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. Notably, say the investigators, animals receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19. The experimental vaccine also induced Th1 T-cell responses but not Th2 responses. Induction of Th2 responses has been associated with a phenomenon called vaccine-associated enhancement of respiratory disease (VAERD). Vaccine-induced Th1 responses have not been associated with VAERD for other respiratory diseases. In addition, the experimental vaccine induced T follicular helper T-cell responses that may have contributed to the robust antibody response.

Four weeks after the second injection, all the macaques were exposed to SARS-CoV-2 via both the nose and the lungs. Remarkably, after two days, no replicating virus was detectable in the lungs of seven out of eight of the macaques in both vaccinated groups, while all eight placebo-injected animals continued to have replicating virus in the lung. Moreover, none of the eight macaques vaccinated with 100 µg of mRNA-1273 had detectable virus in their noses two days after virus exposure. This is the first time an experimental COVID-19 vaccine tested in nonhuman primates has been shown to produce such rapid viral control in the upper airway, the investigators note. A COVID-19 vaccine that reduces viral replication in the lungs would limit disease in the individual, while reducing shedding in the upper airway would potentially lessen transmission of SARS-CoV-2 and consequently reduce the spread of disease, they add. 

Original study published in New England J. of Medicine (July 28, 2020):

https://doi.org/10.1056/NEJMoa2024671 

Microbes living in the rectum could make a difference to the effectiveness of experimental HIV vaccines, according to researchers at the University of California, Davis. The work is published Dec. 11 in the journal mSphere. Evidence from human and animal studies with other vaccines suggests that Lactobacillus supplements can boost production of antibodies, while treatment with antibiotics can hamper beneficial immune responses, said Smita Iyer, assistant professor at the UC Davis Center for Immunology and Infectious Diseases and School of Veterinary Medicine. Iyer, graduate student Sonny Elizaldi and colleagues wanted to know if microbes living in the rectum and vagina — sites of HIV transmission — interacted with an experimental HIV vaccine similar to the HVTN 111 vaccine currently in early stage clinical trials in humans. HVTN 111 includes two doses of HIV DNA snippets and a final boost with an HIV protein, all given through the skin. A vaccine that produces antibodies at the mucosal membranes where infection takes place is thought to be important in preventing HIV infection, Iyer said. The team studied vaginal and rectal microbes from rhesus macaques before and after they were vaccinated. They found that vaginal microbes did not show much difference before and after vaccination. However, rectal microbes did show changes, with Bacteroidetes-type bacteria, especially Prevotella, decreasing after vaccination. 

Lactobacillus bacteria and better immune response

The common gut bacteria Lactobacillus and Clostridia did not change with vaccination, but the amounts of these microbes in the rectum did correlate with the immune response. Animals with high levels of either Lactobacillus or Clostridia made more antibodies to the HIV proteins gp120 and gp140, the researchers found. Prevotella bacteria showed the opposite pattern: High levels of Prevotella were correlated with weaker immune responses. It’s not clear what the mechanism could be for some bacteria to boost local immune responses in a specific site in the body, Iyer said. However, targeting these bacteria could be important to get the best possible performance out of vaccines that do not induce a particularly strong immune response, as is the case with HIV. The microbiome could also be an important but overlooked factor to consider when evaluating vaccines in humans or animals, she said. 

Published in mSphere (December 11, 2019):

https://doi.org/10.1128/mSphere.00824-19