Virus World

Yet another experimental HIV vaccine has failed. The National Institute of Allergy and Infectious Diseases reported Wednesday that a phase 3 clinical trial of an HIV vaccine was stopped because the vaccine was ineffective at preventing infection. The vaccine was being developed by Janssen, the vaccine division of Johnson & Johnson. The Mosaico trial, which enrolled 3,900 volunteers in multiple countries, was halted after a scheduled data review by a data and safety monitoring board found there were roughly as many new HIV infections among people in the vaccine arm as in the placebo arm. The trial was studying the vaccine in cisgender men and transgender people who have sex with cisgender men and/or transgender people. “We are disappointed with this outcome and stand in solidarity with the people and communities vulnerable to and affected by HIV,” Penny Heaton, Janssen’s global therapeutic area head for vaccines, said in a statement. “We remain steadfast in our commitment to advancing innovation in HIV, and we hope the data from Mosaico will provide insights for future efforts to develop a safe and effective vaccine.” In 2021, a Phase 2b trial of a similar candidate HIV vaccine was halted when a data and safety monitoring board determined that it was not preventing infections. The Imbokodo trial was studying the vaccine in women in sub-Saharan Africa.

“For our research partners and others who have waged a decades-long effort to develop vaccines to end the HIV/AIDS pandemic, these results are disappointing,” Susan Buchbinder, co-chair of the Mosaico trial, said in a statement. “Although HIV continues to prove uniquely challenging for development of a vaccine, the HIV research community remains fully committed to doing just that, and each study brings us a step closer to this realization,” she said. Buchbinder is director of Bridge HIV, a grant-funded research unit at the San Francisco Department of Public Health, and a clinical professor at the University of California, San Francisco. The trial was conducted by the HIV Vaccine Clinical Trials Network based at the Fred Hutchinson Cancer Center in Seattle. Veteran HIV vaccine trialist Larry Corey acknowledged yet another setback in the decades-long quest to find an effective HIV vaccine. “HIV is a constantly changing and very challenging adversary. We can become disappointed when our best efforts don’t produce the results we’re looking for,” said Corey, principal investigator of the network’s leadership and operations center. “We have, however, come a long way and made many discoveries since the time when life expectancy was very short following an HIV diagnosis.” The vaccine was based on “mosaic” immunogens targeting HIV subtypes. The goal was to induce immune responses to a broad range of HIV strains. It was given in four injections over the course of a year. The vaccine used the same antigen delivery system employed by J&J’s Covid-19 vaccine, a common cold virus known as adenovirus 26. Volunteers were enrolled in the trial only after they were offered HIV pre-exposure prophylaxis, the antiretroviral drugs that can prevent infection. Those who accepted PrEP were steered towards services where they could access the drugs. People who did not want them, however, were considered for the study. Anyone in the trial who later changed their mind and wanted to use PrEP was also given access to the drugs, but remained in the trial.

At least five experimental HIV vaccines, tested over nine trials, have failed to show efficacy at the Phase 3 stage of development, said Mitchell Warren, executive director of AVAC, the AIDS Vaccine Advocacy Coalition. This latest failure hangs a big question mark over this field of research, he suggested. “I’m not sure we know exactly where the next big investment is going to come from because there’s not an obvious vaccine candidate in HIV that is next up in our efficacy pipeline,” Warren said. “This is another reason why this result is disappointing. This was the last true product in development. And the other activities in the field, which are very exciting … [are] quite upstream. Important upstream science, but not products that are going to be in efficacy trials anytime soon.” Stephaun Wallace, director of external relations for the HIV Vaccine Trials Network, noted work is being done on a candidate HIV vaccine using messenger RNA, the platform successfully used by Pfizer and its partner BioNTech as well as by Moderna to create their Covid-19 vaccines. The HIV work uses the Moderna platform. Exploration of the mRNA platform as a possible basis for an HIV vaccine is still in the safety testing phase, he said. Warren questioned, though, whether the answer is a different vaccine delivery system, suggesting the problem is probably the immune targets at which the various vaccines have aimed. He noted, for instance, that the J&J platform — adenovirus 26 — worked against Covid, but not against HIV. “These are the harsh reminders that it’s not that we don’t have great [vaccine] platforms,” he said. “Our challenge is figuring out exactly what is the target, what is the insert? … We have the vehicles. We don’t even know what passengers to put in the vehicles.” Wallace acknowledged the path ahead will be difficult, but said he remains optimistic that at some point, HIV vaccine efforts will meet success. “I’m pretty certain that with continued public support and interest in this area that we will see the day that an HIV vaccine is developed,” he said.

With as much turmoil and negativity as the COVID-19 pandemic has supplied, there may be a silver lining when it comes to a new vaccine study for those suffering with HIV. The first study participant has been enrolled in a new Phase 1 clinical trial using the messenger ribonucleic acid, or mRNA, vaccine technology developed by Moderna to evaluate the safety and immune responses of three different experimental vaccines against HIV. This randomized, open-label trial represents one of the first clinical studies of the use of mRNA vaccine technology against HIV. The University of Alabama at Birmingham enrolled the trial’s second participant and has enrolled several others since.

Paul Goepfert, M.D., director of the Alabama Vaccine Research Clinic in the Marnix E. Heersink School of Medicine, says the emergence of mRNA vaccines to combat COVID-19 certainly helped move this mRNA HIV vaccine trial along. “Despite tremendous advancements in treatment and prevention of HIV, we still do not have an effective vaccine and thousands of Americans continue to be infected every year,” Goepfert said. “mRNA technology enables a much more rapid development of vaccines that was not previously possible. This new technology will certainly decrease the time it will take to develop an effective HIV vaccine.” The study, HVTN 302, will enroll up to 108 HIV-negative adults. The primary study hypothesis is that the mRNA vaccines will be safe and well-tolerated among HIV-negative people and will elicit neutralizing antibodies.

The experimental vaccines carry mRNA, a piece of genetic code, delivered with instructions for making proteins in the same way that the mRNA vaccines against COVID-19 instruct the body’s cells to make the SARS-CoV-2 spike protein. These instructions show human muscle cells how to make small portions of proteins that resemble parts of HIV but are not the actual virus. People cannot contract HIV from the vaccines. Once immune cells have used the instructions, the mRNA is quickly broken down, and does not stay in the body. The investigational vaccines are not expected to provide protection from HIV infection, yet the knowledge gained from this study will aid in the future development of an HIV vaccine regimen. Researchers hope to learn whether the immune system will respond to the experimental vaccines by making antibodies and T cells that could fight HIV if a person is ever exposed to the virus in the future. The trial will also clarify whether the immune response to an mRNA vaccine is equal to or better than the response to a protein-based vaccine, while helping define the potentials of using mRNA to increase the pace of developing an HIV vaccine. UAB is one of 10 sites nationwide, and the sole site in the South, to enroll participants. At UAB, Goepfert holds the Edward W. Hook, III, M.D., Endowed Professorship in Infectious Diseases. 

J&J's HIV vaccine, using the same technology as its COVID vaccine, failed to meet its goal of reducing the chance of HIV infection by 50%. An HIV vaccine using the same basic technology as Johnson & Johnson’s Covid shot failed to prevent infection, the company said Tuesday, dealing yet another blow to efforts to create a vaccine against the virus.  The study, called Imbokodo, enrolled 2,600 women in southern Africa who were at very high risk of HIV infection. J&J and its partners, including the National Institutes of Health and the Bill & Melinda Gates Foundation, launched the study in 2017 and announced that all participants had received either a vaccine or a placebo last year. The goal of the vaccine was not to completely prevent infection, but to reduce the chance of infection by half. “If a vaccine is 50% efficacious it can curb the future of the HIV pandemic,” said Paul Stoffels, J&J’s chief scientific officer and, before that, an HIV researcher. He said that the actual efficacy seen was 25.2%, meaning those that received the vaccine had their odds of becoming infected reduced that much compared to the placebo group 24 months after the first dose. That difference was not statistically significant, indicating that it is possible the result is due to chance. A second study, called Mosaico, that is testing a somewhat different vaccine regimen in men who have sex with men and transgender people in the Americas and Europe, will continue. 

“The development of a safe and effective vaccine to prevent HIV infection has proven to be a formidable scientific challenge,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said in a statement. “Although this is certainly not the study outcome for which we had hoped, we must apply the knowledge learned from the Imbokodo trial and continue our efforts to find a vaccine that will be protective against HIV.” Scientists have been trying for decades to develop an HIV vaccine. After a Merck vaccine failed to prove effective in 2007, researchers looked back at the data and found it raised the risk of people developing the disease. Hopes were buoyed by a 2009 study in Thailand, which showed limited but significant efficacy, reducing the rate of infection by about 30%. But last year, an effort combining vaccines from Sanofi and GlaxoSmithKline also failed to prove effective.  J&J had repeatedly expressed optimism about its vaccine. In 2015, Johan Van Hoof, who leads J&J’s vaccine R&D, pointed to data showing that, in animals, the vaccine could reduce infection by 90%, “suggesting it might be a real breakthrough with regard to a future HIV vaccine.” On calls with financial analysts in 2020 and 2021, Stoffels listed the HIV project among the company’s vaccine efforts, calling it “very encouraging.” When the trial began five years ago, Fauci had said “the development and delivery of a preventive HIV vaccine that is safe and at least moderately effective would help bring about a durable end to the HIV/AIDS pandemic.” Imbokodo means “rock” in isiZulu, and refers to a proverb about women’s strength and the need for community. In the study, 63 of 1,109 volunteers in the placebo group developed HIV, while 51 of the 1,079 volunteers who received the vaccine developed HIV. That difference leaves a great deal of uncertainty as to whether there was an effect. The 95% confidence interval, used by researchers to define a range of likely outcomes, ranged from -10.5% to 49.3%. However, J&J said in its release that no vaccine-related safety issues were identified. Stoffels told STAT that it was clear the vaccine did not increase the risk of HIV.  Larry Corey, the principal investigator of the HIV Trials Network, which helped run the study, and a professor at the Fred Hutchinson Cancer Research Center in Seattle, said that he saw the result as a disappointment but also a sign of progress. It had been hoped that non-neutralizing antibodies – those that bound to the virus but did not entirely stop infectivity – would be enough to slow the rate of HIV infection, he said, but it is beginning to appear that vaccine developers will need to figure out how to generate antibodies that neutralize the virus.

“It is telling us that non-neutralizing antibodies are not decreasing acquisition and maybe demonstrates how difficult and different HIV is than Covid-19,” Corey said. Like the Covid-19 vaccine that Johnson & Johnson developed, this HIV vaccine delivers genetic code for proteins to a recipient’s cells using a type of virus called an adenovirus, which then makes proteins that the immune system learns to recognize and attack. The strain of adenovirus used, called Ad26, is also used in Johnson & Johnson’s experimental vaccine against respiratory syncytial virus, which can be very serious in infants.  The HIV vaccine regimen tested repeated dosing. It was given four times, and included genetic code for a “mosaic” of proteins from different strains of the HIV virus. Patients also received soluble protein injections at the third and fourth visit. The ongoing Mosaico study – the one in the Americas and Europe – uses a different mixture of soluble proteins at the vaccination visits three and four. Stoffels said that this is one reason that the vaccine might perform better in that study. Another is that the volunteers in the Mosaico study are at lower risk of infection, which may make the vaccine’s work less difficult. Corey also said there was hope Mosaico would succeed where Imbokodo failed. He said that the new formulation had led, in earlier studies, to higher levels of antibodies against HIV. Stoffels said that he doesn’t believe that the result should color people’s feelings about J&J’s adenovirus vaccine platform, which, he pointed out, has proven effective against Covid-19 and Ebola. (In Covid-19, the broad use of the vaccine also was linked to a rare but severe side effect that involves both the formation of clots and excessive bleeding. That side effect is so rare even large clinical trials might not detect it.) “It shows again that the HIV virus is a very special virus, very unique, escaping the immune system and finding its way to infect people and it’s very difficult to mount immunity against acquisition of HIV,” Stoffels said. But researchers will continue to try. Moderna recently began human trials of an HIV vaccine that relies on the mRNA technology behind its Covid vaccines. Corey pointed out that even under Covid lockdowns, women in the study still had a 4% chance of contracting HIV. That underscores the need for a vaccine, he said. “Vaccines really do make a difference when you have an effective vaccine, look at what happened with Covid,” Corey said. “I think we can’t give up.”

Investigators believe that an effective HIV vaccine would need to produce broadly neutralizing antibodies that would work on different strains of the virus. A phase 1 trial of a novel approach for HIV vaccination successfully stimulated production of rare immune cells needed to start the process of generating antibodies against the virus. Notably, the targeted response was detected in 97% of participants who received the vaccine, according to a press release. This study demonstrates proof of principle for a new vaccine concept for HIV, a concept that could be applied to other pathogens, as well,” said William Schief, PhD, whose laboratory developed the vaccine, in a press release. “With our many collaborators on the study team, we showed that vaccines can be designed to stimulate rare immune cells with specific properties, and this targeted stimulation can be very efficient in humans. We believe this approach will be key to making an HIV vaccine and possibly important for making vaccines against other pathogens.”

HIV affects more than 38 million people globally and is known to be one of the most difficult viruses to target with a vaccine. One of the major challenges is because the virus constantly evolves into different strains to evade the immune system. Investigators have worked for decades to create a vaccine that would stimulate the immune system to create rare but powerful antibodies called broadly neutralizing antibodies (bnAbs). According to the press release, bnAbs are specialized blood proteins that could attach to HIV spikes and disable them via important yet difficult-to-access regions that don’t vary much from strain to strain. “We and others postulated many years ago that in order to induce bnAbs, you must start the process by triggering the right B cells—cells that have special properties giving them potential to develop into bnAb-secreting cells,” Schief explained in the press release. “In this trial, the targeted cells were only about 1 in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this.”

The strategy of targeting naïve B cells with specific properties is called germline-targeting, because these young B cells display germline genes. Investigators believe the approach could also be applied to vaccines for other challenging pathogens, such as influenza, dengue, Zika, hepatitis C virus, and malaria. The clinical trial, IAVI G001, enrolled 48 healthy adult volunteers who received either a placebo or 2 doses of the vaccine compound along with an adjuvant developed by GSK. According to the investigators, the novel design, the clinical trial, and the molecular B cell analyses provide a roadmap for further progress in an HIV vaccine. “This is a tremendous achievement for vaccine science as a whole,” said Dennis Burton, PhD, scientific director of the IAVI Neutralizing Antibody Center and director of the NIH Consortium for HIV/AIDS Vaccine Development, in a press release. “This clinical trial has shown that we can drive immune responses in predictable ways to make new and better vaccines, and not just for HIV. We believe this type of vaccine engineering can be applied more broadly, bringing about a new day in vaccinology.”

February 3, 2021:  https://www.scripps.edu/news-and-events/press-room/2021/20210203-hiv-vaccine.html. 

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.....

An experimental HIV vaccine that targets more strains of the virus than any other developed so far will start a late-stage clinical trial later this year. The ‘mosaic’ vaccine, which incorporates genetic material from HIV strains from around the world, also seems to have the longest-lasting effects of any others tested in people.

Small trials of the mosaic vaccine in people showed that it prompted an immune response, such as the production of antibodies, against HIV. But starting in September, scientists will test it in thousands of people to assess whether the vaccine provides any protection against HIV infection. The phase III trial will test the vaccine in transgender individuals and in men who have sex with men across the Americas and Europe. These communities are disproportionately affected by HIV, with about two-thirds of new infections in the United States occurring among gay and bisexual men, according to the US Centers for Disease Control and Prevention. The team running the trial, which they’ve named Mosaico, discussed the project during the 10th International AIDS Society Conference on HIV Science in Mexico City last week.

More than 100 HIV vaccines have been tested in people in the past three decades, but only one has demonstrated any kind of protection. In 2009, researchers announced the results of a study conducted in Thailand that showed that shortly after participants received an experimental vaccine, they were almost 60% less likely to become infected with HIV than those given a placebo. But the effects waned within a year — by the end of the 3.5-year study, vaccinated individuals were only 31% less likely to become infected. Small laboratory tests of the Mosaico vaccine in people showed that it elicited strong immune responses for at least two years after researchers administered it. These responses seem to be more durable than those observed in the Thai vaccine trial, says Guido Silvestri, an AIDS researcher at Emory University in Atlanta, Georgia. The latest Mosaico study will enrol 3,800 participants across 8 countries, including Argentina, Italy, Mexico, Poland and the United States. Half of the participants will get four vaccine injections over the course of a year, and the other half will receive a placebo.

News published on July 31 2019 in Nature:

https://doi.org/10.1038/d41586-019-02319-8

A promising vaccine that clears an HIV-like virus from monkeys is closer to human testing after a new, weakened version of the vaccine has been shown to provide similar protection as its original version.

The vaccine uses a form of the common herpes virus cytomegalovirus, or CMV—was live-attenuated, or weakened so CMV couldn't spread as easily. The new version still managed to eliminate SIV, the monkey version of HIV, in 59 percent of vaccinated rhesus macaques. That result is similar to earlier findings involving the vaccine's original, non-attenuated version. The immunity generated by the attenuated vaccine was also long-lasting, as nine of 12 vaccinated monkeys could still fight off SIV infection three years later.

"These papers are important because they recapitulate the previously reported unique CMV vector efficacy with a genetically modified vector that is highly attenuated and therefore potentially safer for clinical  use" said Louis Picker, M.D., a corresponding author on both papers. "In addition, this new work demonstrates most vaccinated rhesus monkeys that are protected against SIV can also be protected against a second challenge years after initial vaccination. This is a level of durability that would be very important for a human HIV vaccine". The CMV vaccine platform has been licensed by Vir Biotechnology, Inc., of San Francisco, which plans to lead a clinical trial with a human version of the CMV-based HIV vaccine. 

The studies were published on July 17 on Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.aaw2607

https://doi.org/10.1126/scitranslmed.aaw2603 

HIVACAT T-cell immunogen (HTI) is a novel human immunodeficiency virus (HIV) vaccine immunogen designed to elicit cellular immune responses to HIV targets associated with viral control in humans. The AELIX-002 trial was a randomized, placebo-controlled trial to evaluate as a primary objective the safety of a combination of DNA.HTI (D), MVA.HTI (M) and ChAdOx1.HTI (C) vaccines in 45 early-antiretroviral (ART)-treated individuals (44 men, 1 woman; NCT03204617). Secondary objectives included T-cell immunogenicity, the effect on viral rebound and the safety of an antiretroviral treatment interruption (ATI). Adverse events were mostly mild and transient. No related serious adverse events were observed. We show here that HTI vaccines were able to induce strong, polyfunctional and broad CD4 and CD8 T-cell responses.

All participants experienced detectable viral rebound during ATI, and resumed ART when plasma HIV-1 viral load reached either >100,000 copies ml−1, >10,000 copies ml−1 for eight consecutive weeks, or after 24 weeks of ATI. In post-hoc analyses, HTI vaccines were associated with a prolonged time off ART in vaccinees without beneficial HLA (human leukocyte antigen) class I alleles. Plasma viral load at the end of ATI and time off ART positively correlated with vaccine-induced HTI-specific T-cell responses at ART cessation. Despite limited efficacy of the vaccines in preventing viral rebound, their ability to elicit robust T-cell responses towards HTI may be beneficial in combination cure strategies, which are currently being tested in clinical trials. Vaccines that elicit HIV-specific T-cell responses did not prevent viral rebound in people living with HIV upon antiretroviral treatment (ART) interruption, but associated with longer time off ART in some trial participants, suggesting their immunogenicity may benefit future cure approaches.

Published In Nature Medicine (Oct. 27, 2022):

https://doi.org/10.1038/s41591-022-02060-2 

mRNA technology may be uniquely positioned to tackle a major hurdle for HIV vaccines: the elicitation of broadly cross-reactive neutralizing antibodies. A preclinical study takes the first step toward this goal.  The remarkable success of mRNA vaccines against COVID-19 has been nothing short of miraculous. Whether this unique technology platform can be used to tackle the more complex task of developing a vaccine against human immunodeficiency virus (HIV) is now under intense scrutiny. In this issue of Nature Medicine, a preclinical study by Zhang et al. suggests that the mRNA platform may be up to the challenge1. The authors encapsulated mRNA encoding the HIV envelope glycoprotein (Env) (the equivalent of the SARS-CoV-2 spike protein), together with the structural HIV group-specific antigen protein (Gag), in a lipid nanoparticle, to produce virus-like particles (VLPs) in vivo. These Env-expressing VLPs elicited broadly neutralizing antibodies (bNAbs) and other immune responses that were protective against viral challenge in a macaque model. Although the VLPs were not nearly as immunogenic or as efficacious as mRNA vaccines against COVID-19, these results are encouraging and illuminate a pathway toward inducing the higher and more-durable antibody responses needed to prevent infection with HIV. This is no small feat; Env is a formidable target that fails to induce the right kind of antibodies even in the majority of people who are infected with HIV. Unlike spike protein, which is relatively stable and contains just a few immunodominant epitopes (mostly restricted to the receptor-binding domain), Env is a complex trimeric protein with multiple dispersed antibody epitopes — many of which are conformational and heavily coated in sugars that shield them from antibody attack (Fig. 1). The ability to generate soluble trimeric Env proteins through the introduction of key mutations was a major advance in immunogen design, although these so-called ‘SOSIP proteins’ induced only autologous strain–specific neutralizing antibodies2. In the present study by Zhang et al., antibodies elicited by the Env–Gag mRNA were able to neutralize almost all members of a global panel of HIV isolates, classified as having a tier 2 phenotype1. This represents a major step forward for a vaccine against HIV, as this phenotype is typical of most circulating strains, which are difficult to neutralize due to a closed Env conformation.

It is likely that a number of factors contributed to the greater immunogenicity of the mRNA vaccine designed by Zhang et al.1. The endogenous expression of the native Env on the surface of a VLP would preserve conformational epitopes, and VLPs were also shown to contain double the number of Env molecules present in an HIV viral particle. Furthermore, mRNA continues to be expressed for several days after administration, providing ongoing immunostimulation3. Another potential advantage is the ability of VLPs to bind to antigen-presenting cells, which guarantees delivery of mRNA into the appropriate cells and the induction of follicular helper T cells that are crucial for B cell development in germinal centers4. Zhang et al. also chose an HIV Env sequence that lacks a glycan at position 276; this enabled better access to the B cell precursors of bNAbs that target the CD4-binding site on the viral envelope1. Indeed, Env–Gag mRNA elicited antibodies to that site and, interestingly, to many other HIV epitopes — a considerable improvement on the strain-specific ‘glycan-hole’ responses seen with SOSIP proteins. It will be important in future studies to isolate B cells from mRNA-immunized animals to ascertain whether they are capable of broad neutralization and if they carry the genetic features associated with known bNAb lineages. Although the results from Zhang et al.1 are encouraging for the HIV vaccine field, this is a complex and impractical protocol that requires multiple immunizations with high doses of mRNA. Moreover, the levels of bNAbs elicited in this study were extremely low and took a year to develop, and their role in protection from infection remains unclear. mRNA technology has only recently come of age; it was originally hampered by instability and unfavorable immunogenicity, but decades of research have solved these problems, and the advantages of mRNA as a vaccine platform continue to emerge5. These include rapid development, ease of manufacture and scalability, which offer advantages over the traditional vector-based or protein-based vaccines being pursued in the HIV field. For example, mRNA would enable testing of sequential immunization and lineage-based approaches that require multiple immunogens with minor but important sequence changes6. mRNA is also considerably cheaper to produce and can be modified as needed, an important consideration for rapidly mutating viruses like HIV. Among the vaccines against COVID-19, those based on the mRNA platform have superior immunogenicity and stimulate both B cell responses and T cell responses7,8. The precise mechanisms underlying mRNA immunogenicity, however, are still unknown, and much remains to be learned if they are to be optimized and applied to HIV prevention. Nonetheless, the vast amount of safety data available from mRNA vaccines against COVID-19 will probably contribute to streamlined regulatory approval processes for vaccines against HIV and other diseases.

Participants in the trial must be between the ages of 18 and 50 and not diagnosed with HIV.  Moderna is set to start human trials for its experimental mRNA HIV vaccine as early as Thursday, the first time such a trial has ever been conducted. 

The big picture: "There's a pressing need for new ways to prevent infection from viruses like HIV and influenza that conventional vaccines have struggled to address and to treat rare genetic diseases and cancers that kill millions each year," Axios' Alison Snyder writes. "Vaccines and therapies based on messenger RNA (mRNA) hold promise as a solution."

Details: To participate in the trial, participants have to be between the ages of 18 and 50 and not diagnosed with HIV. Moderna says it is looking for 56 participants.

What they're saying: "Even as we have shown that our mRNA-based vaccine can prevent Covid-19, this has encouraged us to pursue more-ambitious development programs within our prophylactic vaccines modality," said Moderna CEO Stéphane Bancel in January, when the company announced the vaccine, per Clinical Trials Arena.

The UNAIDS estimates that 38 million people currently live with human immunodeficiency virus (HIV) infection. Combination antiretroviral treatment has had great success in saving lives but is also associated with numerous medical and public health challenges. Vaccination remains the best and most cost-effective option for controlling HIV infection across the world. Professor Tomáš Hanke jointly from the University of Oxford, UK, and Kumamoto University, Japan, designs vaccines and coordinates clinical programs testing the most advanced vaccine candidates developed by his team in the UK, Europe, U.S. and Africa.

Ending AIDS with vaccination

Human immunodeficiency virus (HIV) type 1 represents 95% of all HIV infections worldwide and is responsible for the global HIV pandemic. If untreated, HIV-infected patients develop acquired immunodeficiency syndrome—better known as AIDS—that manifests as a progressive failure of their immune system. As a result, patients eventually succumb to opportunistic infections. Combination antiretroviral treatment (cART) has transformed the lives of people living with HIV, and dramatically decreased AIDS-related mortality and onward transmission of HIV. Unfortunately, the provision of cART to everybody who needs it faces many obstacles particularly in low- and middle-income countries. The cost, complexity of the treatment, necessity of regular monitoring of patients, threat of drug resistance, side effects, social stigma and the use of cART to prevent HIV infections (or pre-exposure prophylaxis), which further stretches the cART supply, make cART a suboptimal therapeutic and an unlikely stand-alone tool to end the HIV epidemic. Therefore, an effective vaccine for both prevention and cure of HIV is urgently needed. 

Professor Tomáš Hanke and his team at the Jenner Institute at the University of Oxford, UK, together with their collaborators at the Joint Research Center for Human Retrovirus Infection, Kumamoto University, Japan, are studying T cell responses to HIV to inform vaccine development. In addition, Professor Hanke oversees Experimental Medicine trials of his leading T-cell vaccine candidates in healthy and HIV-positive people at several global sites and collaborates with prestigious universities and organizations such as the International AIDS Vaccine Initiative, IrsiCaixa AIDS Research Institute-HIVACAT in Spain, Imperial College London, the Kenya AIDS Vaccine Initiative-Institute for Clinical Research and National Institute of Allergy and Infectious Diseases. He also co-ordinates the "Globally Relevant AIDS Vaccine Europe-Africa Trials Partnership" consortium, acronymed GREAT, which builds research capacity and tests vaccine candidates in Eastern and Southern Africa, and is one of the principal investigators of the European AIDS Vaccine Initiative 2020.

An experimental HIV vaccine developed by scientists at Scripps Research and the nonprofit vaccine research organization IAVI has reached an important milestone by eliciting antibodies that can neutralize a wide variety of HIV strains. The tests, in rabbits, showed that these "broadly neutralizing" antibodies, or bnAbs, targeted at least two critical sites on the virus. Researchers widely assume that a vaccine must elicit bnAbs to multiple sites on HIV if it is to provide robust protection against this ever-changing virus. The promising results, which appear in Immunity, suggest that researchers are one step closer to developing an effective HIV vaccine--a major goal of medical science ever since the virus was identified in 1983. 

According to UNAIDS, about 35 million people worldwide have died of the immunodeficiency syndrome, AIDS, which is caused by HIV infection. About 38 million others are now living with HIV infection. Antiviral drugs can keep HIV-infected people alive and reduce their ability to transmit the virus to others, but these drugs do not clear the infection and must be taken indefinitely. Researchers have long recognized that a preventive vaccine, available at a low cost to uninfected people, will be needed to eliminate HIV as a major public health threat. HIV's rapid mutation rate and other mechanisms for evading immune attack have made it an extremely difficult target for vaccine designers. But the test conducted by Wyatt and his team confirms that vaccination can elicit the kinds of antibodies that are needed to provide broad protection against HIV. These bnAbs, as vaccine experts call them, can neutralize multiple HIV strains because they bind to critical sites on the virus that do not vary much from strain to strain. People who are infected with HIV sometimes produce bnAbs as part of their antibody response, but infrequently and usually after infection has been long established. The chief challenge for HIV vaccine designers has been to find ways to stimulate the immune system--in most or all individuals--into making bnAbs that hit multiple vulnerable sites on the virus, in order to protect against a high proportion of HIV strains.

At the heart of the vaccine design by Wyatt and colleagues is a virus-mimicking protein based on HIV's "Env" protein. Normally, multiple copies of bush-like Env proteins are spread out on the surface of each spherical HIV particle. Each Env protein contains a molecular mechanism that allows it to bind to a receptor on immune cells known as CD4, and use that receptor as a portal to break into the cell. The researchers engineered a version of Env that models the essential structures on the real Env while being stable enough to use as a vaccine. To present it in a way that would resemble a real HIV virus particle, they created virus-sized synthetic spheres of fat-related molecules, "liposomes," which are studded densely with the engineered Env proteins. On a natural HIV Env protein, thickets of sugar-related molecules called glycans normally help shield the all-important CD4 binding site from immune attack. As an initial "priming" immunization, the researchers used versions of Env in which this glycan shield around the CD4 binding site had been partly removed. "The idea was to better expose this site and thereby stimulate a broad antibody reaction to it at the start," Wyatt says.

Subsequent booster immunizations over 48 weeks used Env proteins with restored glycans, to select for antibodies that target the CD4 binding site but can also get through this shield. The Env proteins in the booster shots also were mixes based on different strains of HIV, to generally promote antibody responses against Env structures that do not vary among these strains. The team inoculated 12 rabbits following their vaccine strategy and compared the results with a control group that received only a single, glycan-shielded version of Env. They found that their vaccine strategy had a much better response, with five of the rabbits developing antibodies that could neutralize multiple HIV isolates...

Published in the J.  Immunology (Nov. 12, 2019):

https://doi.org/10.1016/j.immuni.2019.10.008

Efforts to develop an effective HIV vaccine have repeatedly stumbled on one tough research strain, SIVmac239. Nicknamed the 'death star' strain, it has defeated multiple anti-HIV vaccine and antibody candidates, until now. Scientists have just beaten the 'death star' with a gene-therapy-style, nontraditional vaccine that prompts muscle cells to manufacture protective proteins.

A team at the Scripps Research Florida campus reports successfully beating that challenge. In a paper published in the journal Science Translational Medicine today, lead authors Michael Farzan, PhD, and Mathew Gardner, PhD, describe their destruction of the "death star" strain and another especially hard-to-fight strain, suggesting it may be possible to protect uninfected individuals from multiple forms of HIV.

Their nontraditional vaccine achieved another critical goal: durability. This means it protected the research animals from infection long-term, with a single inoculation, Farzan says.  "We have solved two problems that have plagued HIV vaccine studies to date -- namely, the absence of duration of response and the absence of breadth of response," Farzan says. "No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection." 

Conventional vaccine approaches typically use a piece of virus or other immunogen to activate an immune system response. Because HIV replicates and changes so quickly, that approach has proven challenging. Farzan's approach uses a safe virus to fight the dangerous one, and relies on muscle cells rather than immune cells to generate protective agents. Here's how: A harmless, lab-made adeno-associated virus (AAV) carries within it a protective protein designed by Farzan and colleagues to stop HIV infectivity. Called eCD4-Ig, the protective protein features two HIV co-receptors, CD4 and CCR5. The latter was discovered by Farzan and his team over a decade ago. Farzan's viral vaccine is injected into muscle. It "infects" the muscle cells, which causes them to produce the protective eCD4-Ig. During exposure to HIV, the HIV virus is attracted to eCD4-Ig. It binds, and then "undergoes conformational change prematurely, and it's no longer able to infect," Farzan says....

The study was published  on July 24 in the journal Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.aau5409