Contagion Editorial Team

There is a small group of PLWH who are known as controllers and they can suppress HIV naturally with the help of their body’s cytotoxic T (CD8+ ) cells. When immune responses are working, cytotoxic T cells recognize antigens, which are found on the surface of infected cells, and the T cells then kill the infected cells and destroy the virus.

However, a small new study shows that when the cytotoxic T cells lose the ability to proliferate and kill HIV-infected cells, these PLWH no longer can suppress the virus naturally, and need antiretrovirals (ART) to control it. 

“Loss of proliferation [cytotoxic T cells] was the most consistent predictor of aborted control in our study,” Principal investigator David Collins, PhD, fellow, Ragon Institute of MGH, MIT and Harvard, said. “In these cases, HIV-specific T cells gradually lost their ability to proliferate and become cytolytic, sometimes years before control was lost.”

Collins and the investigators compared samples from HIV controllers at Ragon and the University of California at San Francisco over several years. This small study included 17 subjects with aborted control and 17 with durable control, whose immune systems continued to suppress HIV over years of observation.

The team first looked at antigens and compared what type were presented by infected cells. When the team compared the two groups, they found that both sets of T cells responded to the same types of unlikely-to-mutate antigens.

The investigators looked more closely at the HIV-specific T cells in both groups, focusing on how well the T cells could perform their various functions. Cytotoxic T cells have 2 important functions when they encounter a cell presenting an HIV antigen. The first is their ability to kill infected cells by systematically rupturing them. The second function is their proliferative function: creating more HIV-specific T cells that can then hunt down and kill other infected cells.

In progressors—PLWH who cannot control the virus naturally and who require medication to suppress it—T cells quickly become desensitized to the HIV antigens and stop responding to them, a state known as T cell exhaustion. Researchers thought perhaps a similar process was happening to T cells when control was lost, but they found no such evidence. With the loss of control came a clear dysfunction of the T cells—the inability to kill cells infected by HIV—but it was a different type of dysfunction than was observed in most infections.

In the group of people who lost control of HIV, there was a measurable decrease in the proliferative and cytolytic ability of the T cells seen in samples taken before the loss of control, sometimes even years before. In addition, this dysfunction was only seen in response to HIV; the T cells were able to respond properly to other viral antigens. 

The team next compared the genes expressed by the T cells in the 2 groups and found another important difference, one linked to their earlier observations. The T cells in the loss of control group had increased expression of 

, a gene that, when expressed at high levels, impairs the ability of T cells to proliferate.

“This study shows that loss of control is notably different from the inability to control the virus found in the canonical immune response to HIV,” says Ragon Director Bruce Walker, MD, and the paper’s senior author. “It further underlines the importance of a functional, effective T cell response to HIV in natural immune control of the virus. And with each secret HIV reveals comes an opportunity for us to use that knowledge to our advantage.”

This discovery may work towards treatments and vaccines that could train progressors’ immune systems. Further investigation is needed to understand why T cells become dysfunctional in some people and not in others.

Articles

A small subset of people living with HIV (PLWH) can naturally suppress the virus without medication.

Impaired T Cell Function Can Lead to Loss of Ability to Suppress HIV 

Hospitalized patients with COVID-19 who were treated with convalescent plasma did not see a reduction in the risk of intubation or mortality, according to a new study.

“It has been thought that the blood plasma of COVID-19 survivors would help those seriously ill from the virus but, unfortunately, it does not,” Donald Arnold, co-principal investigator of the study, hematologist and professor of medicine at McMaster University, said. “We are cautioning against using convalescent plasma to treat COVID-19 hospitalized patients, unless they are in a closely-monitored clinical trial.”

The study results were published in the journal 

The clinical trial, called CONCOR-1, stopped enrollment early in January 2021 after its independent data safety monitoring committee recommended the study was unlikely to demonstrate a benefit of convalescent plasma even if more patients were enrolled.

Investigators also found that patients receiving convalescent plasma experienced significantly more serious adverse events than those receiving standard care.The majority of those events were an increased need for oxygen and worsening respiratory failure. However, the rate of fatal incidents was not significantly different from the control group of patients who did not receive the blood.

A secondary discovery was that convalescent plasma had highly variable donor antibody content due to the highly variable immunological response to the virus. Different antibody profiles in the convalescent plasma were observed to significantly impact whether or not patients experienced intubation or death. Unfavorable antibody profiles, meaning low antibody titers, non-functional antibodies or both, was associated with a higher risk of intubation or death.

“These findings may explain the apparent conflicting results between randomized trials showing no benefit, and observational studies showing better outcomes with higher titer products relative to low titer products,” Jeannie Callum, co-principal investigator, associate scientist at the Sunnybrook Research Institute, and professor at Queen’s University and the University of Toronto, said. “It appears that it may not be that high-titer convalescent plasma is helpful, but rather that low-titer convalescent plasma is harmful.”

The antibody profile in the blood of patients who have had the virus is extremely variable and this may modify the response to the treatment.

Convalescent Plasma Does Not Reduce Risk of Intubation, Mortality 

Gaithersburg, MD-based Novavax announced it had begun enrollment for its phase 1/2 study to evaluate the safety and immunogenicity of a combination vaccine using the Novavax seasonal influenza and COVID-19 vaccines.

"This study is the first-of-its-kind to evaluate the vaccine's potential to induce a robust immune response, augmented by our Matrix-M adjuvant, against two life-threatening diseases simultaneously," Gregory M. Glenn, MD, president of Research and Development, Novavax, said. "The combination of these two vaccines, which have individually delivered outstanding results with favorable safety and tolerability profiles, may lead to greater efficiencies for the healthcare system and achieve high levels of protection against COVID-19 and influenza with a single regimen."

Investigators are planning to study 640 healthy adults 50 to 70 years of age. Participants will have been either previously infected with the SARS-CoV-2 virus that causes COVID-19 or vaccinated through an authorized vaccine at least eight weeks prior to enrollment. All participants will be randomly assigned to cohorts to evaluate multiple formulations and will be dosed on Day 0 and again at Day 56. The trial will be conducted in Australia at up to 12 study sites.

Separately, their investigational influenza and COVID-19 vaccines have shown promising results in clinical trials.

NVX-CoV2373 demonstrated 100% protection against moderate and severe COVID-19 infection and 90.4% efficacy overall in phase 3 trial with nearly 30,000 adult participants in the US and Mexico.

NVX-CoV2373 is a protein-based vaccine candidate engineered from the genetic sequence of the first strain of SARS-CoV-2, the virus that causes COVID-19 disease. NVX-CoV2373 was created using Novavax' recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and is formulated with Novavax' patented saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies.

In a phase 3 trial using adults 65 years and older, NanoFlu achieved the primary endpoints, demonstrating non-inferior immunogenicity to a licensed comparator on all four influenza virus strains included in the vaccine, while also showing both enhanced wild-type hemagglutination-inhibiting antibody responses against homologous and multiple heterologous A/H3N2 strains, and potent induction of T cell responses.

The results for this latest study are expected during the first half of 2022.

The shot will be its NanoFlu/NVX-CoV2373 vaccine using the company’s Matrix-M adjuvant platform.

Novavax Begins Phase 1/2 Study for Its Combination COVID-19 and Influenza Vaccine

FluGen, a clinical-stage vaccine company, announced its investigational influenza vaccine candidate, Bris2007 M2SR, induced neutralizing antibodies for participants in its human challenge study against H3N2 influenza strain.

“Current vaccines are strain-specific and in recent years they have had low efficacy against H3N2 influenza, especially when the vaccine is mismatched to circulating virus,” Robert Belshe, MD, the Diana and J. Joseph Adorjan endowed professor of Infectious Diseases and Immunology, Emeritus, at Saint Louis University, and Chair of the FluGen Clinical Advisory Board, said.

The human challenge trial included participants who were aged 18-55 years that were randomized to receive a single intranasal spray, either with placebo or with a 108 TCID50 dose of monovalent H3N2 M2SR vaccine. Four weeks later, they were challenged with an influenza strain 7 years drifted from the vaccine, a period during which WHO recommended four H3N2 vaccine strain changes to maintain match against seasonal influenza virus.

 trials? Read more about the bioethics of such trials and what considerations go into them before commencing.

The challenge study results demonstrated that, despite the significant mismatch of vaccine and challenge strains, a single dose of Bris2007 M2SR induced neutralizing antibody to the vaccine (48% of recipients) and challenge strain (27% of recipients).

Overall, 54% of M2SR subjects were infected after challenge, compared to 71% of placebo subjects. The subset of M2SR subjects with a vaccine-induced microneutralization response against the challenge virus had reduced rates of infection after challenge (38% vs. 71% of placebo subjects, 

In terms of adverse events, they were considered mild and similar in frequency between placebo and M2SR recipients. Most treatment emergent adverse events were mild in severity, and no vaccine virus shedding was detected in any of the subjects. The correlation between serum markers and efficacy in the trial is expected to accelerate further development of M2SR.

The M2SR platform is a supra-seasonal, live, single-replication, intranasal flu vaccine. M2SR stimulates mucosal, humoral, and cellular immunity.

“The M2SR vaccine candidate is designed to induce a broad, multi-effector immune response, and this study demonstrated that subjects with vaccine-induced neutralizing antibodies were protected against infection and illness following challenge with an antigenically drifted virus,” Belshe said. “Inactivated vaccines have not had that broad protection. This is the first demonstration in adults of vaccine-induced protection against a highly drifted H3N2 challenge virus.”




FluGen announced its vaccine candidate, Bris2007 M2SR, induced neutralizing antibodies against infection and illness following a challenge with an antigenically distinct virus.