TAG HIV Research Network Statements: International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network

Background and Achievements

The IMPAACT network is the only research enterprise focused on clinical studies to improve maternal, pediatric, and adolescent health in people with (or at risk for) HIV, tuberculosis (TB), and related conditions. The development of interventions for these populations has a longstanding and damaging history of lagging behind those for nonpregnant adults.

IMPAACT has played an essential role in addressing this lag, conducting studies supporting the licensure of pediatric formulations of new treatments for HIV such as dolutegravir, abacavir, and lamivudine. Recently, IMPAACT 2017 provided results supporting the use of new long-acting antiretroviral therapy (ART) with cabotegravir and rilpivirine in adolescents aged 12 years and older.

The network has also facilitated the licensure of the new TB drug bedaquiline for children; for example, the IMPAACT P1108 bedaquiline trial led to updated global guidelines for the provision of TB care to children and adolescents. IMPAACT is now conducting essential research on pediatric formulations of pretonamid, which are necessary to allow children with drug-resistant TB to benefit from the standard-of-care regimen that adults receive.

The continuation of a dedicated network for addressing pediatric, adolescent, and maternal TB is important given the lack of market incentives for industry to study new medicines in these populations. For example, there were 6–13-year gaps observed between when TB drugs such as delamanid, rifapentine, bedaquiline, and pretomanid were licensed for adults versus when they were (or will be) licensed for children. In the end, studies of these compounds in children were led by IMPAACT and other public-sector research initiatives rather than by pharmaceutical companies. Children represent around 12% of the global burden of TB (1.2 million of the 10 million people who develop TB each year are children) and around 16% of TB deaths (>200,000 each year) but pediatric research makes up less than 10% of all money spent on TB research. The U.S. NIH is the largest funder of pediatric TB research in the world, contributing around one-fourth of total expenditures in this area with the IMPAACT Network being the centerpiece of this investment.

The international distribution of IMPAACT network sites is critical to this work because the successful reduction of HIV transmission from mothers to newborns (made possible by past studies by both ACTG and IMPAACT) means that global research is necessary to recruit enough participants to produce statistically robust findings. The same is true for TB treatment trials among children, which must operate internationally in order to enroll enough children to study new treatment regimens with sufficient precision. Although global in its reach, the IMPAACT network benefits children and families everywhere, including in the United States.

A key current priority for IMPAACT is the pursuit of HIV remission and cure strategies to reduce and hopefully eventually eliminate the need for continuous ART in infants, children, and adolescents living with HIV — populations for which adherence can be particularly challenging. IMPAACT investigators have led the way in pediatric HIV cure research, from involvement in studying the first reported case of extended HIV viral load suppression in an infant after ART interruption (the “Mississippi baby”) to the development and conduct of the large ongoing international P1115 study evaluating whether this type of outcome might be replicable more broadly. At the time of the last report, four infants in the trial have experienced a long period of HIV remission after ART interruption and three have yet to restart.

IMPAACT network research to establish the safety of important therapeutics in pregnancy and postpartum remains ongoing and includes antiretrovirals, TB drugs, long-acting ART, ceftriaxone, benzathine Penicillin G, and glecaprevir/pibrentasvir for hepatitis C.

The network’s prevention agenda includes assessments of the potential of broadly neutralizing antibodies (bNAbs) as an alternative to ART-based prophylaxis against HIV and shortened regimens to prevent TB.

The unique role of the IMPAACT network and its exemplary track record underscores that continued funding support is vital.

TAG Recommendations on Research Priorities

• Continued focus on the development of curative, immunotherapy and remission strategies for infants, children, and adolescents with HIV to benefit individual health, reduce the burden of adherence to antiretroviral therapy (ART), reduce costs, and reduce the complexities of healthcare provision by caregivers and families.
• Development of improved, more convenient, and easier to implement therapeutics for use during pregnancy and postpartum, and for infants, children, and adolescents with HIV.
• Development of improved, more convenient, and easier to implement therapeutics for related diseases and conditions, with a primary focus on tuberculosis (TB) (both with and without HIV coinfection) in infants, children, adolescents, and during pregnancy and postpartum.
• For TB trials, the focus should be on supporting studies necessary for children to benefit from access to the full suite of short-course regimens recommended for the treatment of drug-sensitive and drug-resistant TB in adults and adolescents. This includes completing IMPAACT 2034, a single-dose pediatric pharmacokinetic (PK) and safety study of pretomanid, a step toward ensuring children can benefit from shorter regimens that include the drug. If supported by the results, next steps will need to include multi-dose evaluations of pretomanid.
• Conduct studies and coordinate stakeholders to pursue research to address TB during pregnancy and lactation in pursuit of the objectives of the Consensus Statement: Optimal and Early Inclusion of Pregnant and Lactating Women in Tuberculosis Research.
• Continued research to develop and optimize methods for understanding and addressing mental health complications associated with HIV and related conditions in infants, children, adolescents, and during pregnancy and postpartum.
• Collaborative research with the HVTN, ACTG, and external stakeholders to advance clinical development of new TB vaccines that can prevent TB disease among infants, children, adolescents, and during pregnancy and postpartum (in populations both with and without HIV). Adolescents, pre-adolescents, and younger children remain under-represented in TB vaccine clinical trials (typically justified by low incidence of TB disease in these age groups, which belies the fact that young people get TB and are not always well served by existing preventive and treatment options). Currently, the TB vaccine pipeline contains only one candidate in an active trial among infants (a phase III study of MTBVAC compared to BCG funded by the European Commission).

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TAG HIV Research Network Statements: HIV Vaccine Trials Network (HVTN)

Background and Achievements

The development of an effective HIV vaccine remains both a critical priority and one of the most significant challenges faced by scientists. Unlike most pathogens, HIV infects CD4 T cells, a central coordinator of the immune response, meaning that vaccination must equip the immune system with the ability to fend off an infection of itself (not an infection of the liver or the lung, as is the case for hepatitis B or SARS-CoV-2, for example). HIV integrates its DNA into the genetic code of infected CD4 T cells, making elimination of the virus extremely difficult once established.

The mutability of HIV — which is vastly greater than for influenza virus — adds yet another layer of difficulty: the virus’ outer envelope is a constantly evolving moving target cloaked in decoy sugar molecules called glycans, making it highly resistant to neutralization by antibodies (typically a key contributor to immune protection). The surface of HIV is also sparsely populated with the viral spikes that antibodies must bind to achieve neutralization. The constant mutation of the virus impedes recognition not only by antibodies, but other types of immune responses including those mediated by CD4 and CD8 T cells.

The approval of several antiretrovirals for pre-exposure prophylaxis (PrEP) to prevent HIV acquisition, including the latest twice-yearly option lenacapavir, is a very welcome development but cannot fill the vaccine gap for multiple reasons including costs, drug interactions, side effects, and a prerequisite to recognize the need for PrEP. Approximately half of all new cases of HIV in the United States occur in people who wouldn’t be identified as candidates for PrEP, and in some areas of the world this proportion reaches 75%. A major and unique advantage of vaccines is the potential to offer broad population coverage regardless of self-assessment of HIV exposure risk.

The HVTN has led efforts to translate the best available evidence from laboratory and pre-clinical animal research into clinical testing of experimental HIV vaccine candidates in people, conducting more than 200 studies to date involving 28,000 volunteers globally (nearly 10,000 Americans).

Additionally, the network is making critical contributions to the development of a broadly effective vaccine against tuberculosis, which remains a global scourge and the leading cause of death among people with HIV. The HVTN will remain instrumental in efforts to study the safety and immunogenicity of TB vaccines in PLHIV so that they can be included in phase III efficacy trials and are eligible to benefit if the vaccines achieve licensure. Together with the other HIV research networks, the HVTN was instrumental in developing a series of consensus statements on studying TB vaccines in PLHIV and will be critical to ensuring its recommendations are followed.

Efficacy trials of HIV vaccine candidates that failed to demonstrate sufficient protection against HIV acquisition are sometimes cited in an attempt to cast the field in a poor light, but these were carefully conducted studies based on the evidence available at the time and the urgency of the need. The lessons from this research continue to inform the design of potentially superior candidates, and have focused attention on the importance of solving the stern scientific problem of inducing broadly neutralizing antibody responses (bNAbs) against HIV. Collaborative work between the HVTN and HIV Prevention Trials Network (HPTN) to conduct the Antibody-Mediated Prevention (AMP) trials has formally demonstrated that bNAbs can prevent HIV if present in sufficient amounts and correctly targeted against circulating viral strains.

The HVTN has also led the way in promoting community education and involvement, creating the Red Ribbon Registry for people interested in volunteering for studies and significantly increasing the diversity of participation across demographic groups. The term diversity has recently been targeted for specious political reasons, but broad representation in clinical trials is essential for ensuring interventions are efficacious and can be implemented in diverse populations. This work was foundational to the successful development of COVID-19 vaccines when HVTN and other HIV research networks supported by the National Institutes of Health stepped up to form the COVID-19 Prevention Trials Network (CoVPN) in order to successfully evaluate the vaccine candidates which, despite the avalanche of politically motivated misinformation that has since surrounded them, have saved vast numbers of lives in the U.S. and globally.

TAG’s recently published annual HIV Vaccines and Passive Immunization Pipeline Report lists 30 clinical trials, 15 of which are sponsored by HVTN (in one case, in partnership with the HIV Prevention Trials Network). Our 2024 Tuberculosis Vaccines Pipeline Report shows 17 candidates under clinical development with HVTN participating in trials of MTBVAC and ID93/GLA-SE and poised to contribute to the development of newer candidates such as the novel subunit vaccine H107e/CAF10b.

As HIV vaccine scientist Glenda Gray has stated: “We can’t stop now.” Technological advances are facilitating great progress in understanding how effective antibody responses are generated, bringing scientists ever closer to the development of HIV vaccine candidates with the potential to be broadly effective. This work also has the clear potential to inform vaccine development for multiple other diseases. It’s important to remember that the goal of investing in HIV vaccine research is to not only avert the human cost of the condition, but also the financial burden of lifelong care and treatment.

TAG Recommendations on Research Priorities

We will not be able to completely end the HIV pandemic without a safe, effective, universally accessible and affordable HIV vaccine. Achieving this demands the following:

• Research into strategies for inducing bNAbs in both adult and pediatric populations internationally, including the iterative testing of germline targeting candidates designed to guide B-cells along the pathway to generating effective antibody responses (using mRNA or other appropriate technologies based on science, not mythology and conspiracy theories). Funding should be restored for the HIV vaccine consortia at Duke University and Scripps that were making significant progress in identifying vaccine constructs for clinical testing by HVTN.
• Development and assessment of preventive vaccines for tuberculosis. Continuation of support for international research sites is essential for this work given the epidemiology and global distribution of the TB epidemic.
• Continued collaborative research with other NIH-supported networks and external stakeholders to advance clinical trials of TB vaccine candidates with a focus on generating the evidence required to include PLHIV (of all ages) in TB vaccine prevention-of-disease efficacy trials. Priority candidates positioned for phase II and III trials over the next funding period, and for which data in PLHIV will need to be generated, include live-attenuated vaccines (MTBVAC), protein/adjuvant subunit vaccines (H107e/CAF10b, ID93/GLA-SE), and the first mRNA TB vaccine constructs.
• Continued support of translational science to maximize the value of clinical trial results including participation in discovery of TB vaccine correlates of risk and protection. This should include efforts to develop scientific tools and approaches for facilitating TB vaccine clinical trials such as novel immune assays or frameworks for addressing asymptomatic TB.
• The HVTN should consider adding hepatitis C vaccines to their portfolio when they become available for clinical testing.
• Continued international engagement with communities about vaccine science and trial participation, to ensure the research is conducted in partnership with directly affected and highly affected communities, and to garner information vital to effective implementation of successful HIV and TB vaccines (including maintenance of the Red Ribbon Registry).
• Continued collaborative research with other NIH-supported networks e.g. to assess bNAb-based candidates in people living with HIV, pediatric populations.
• Preservation of HVTN’s vaccine-specific infrastructure and expertise.