For each framing question, the context for each question is provided followed by the consensus statement.
3. Which vaccine candidates should be prioritized for study in people with HIV on ART?
Context: As only a fraction of Mtb infected persons goes on to develop clinical disease, there are two critical time points for prevention using vaccines: pre-infection or post-infection. Pre-infection (POI) vaccine strategies are appropriate for use in newborns in endemic settings or slightly older adolescents in lower burden regions. Post-infection vaccine strategies include POD in Mtb infected persons, therapeutic vaccination in those with TB disease to reduce the proportion of TB patients with unfavourable treatment outcomes, and POR in TB patients who have been successfully treated37. TB vaccine candidates evaluated in people with HIV are summarized in Supplemental Table 1. Viral vectored, subunit adjuvanted and whole cell (killed) TB vaccines induce variable humoral and cellular immunity in people with HIV, although responses in ART naïve persons tend to be poorer.
Consensus statement: For adults and adolescents with HIV, subunit and non-replicating viral vectored vaccines should be prioritized, although inactivated mycobacterial vaccines may also be evaluated in this population. Novel vaccine platforms such as mRNA and DNA should be prioritized for evaluation among people with HIV, including infants and children. We encourage the evaluation of immunogenicity and safety of novel live attenuated vaccines early in development, considering possible risks and benefits for each candidate vaccine (in each age group) in people with HIV on ART. For infants and children with HIV, subunit and viral vectored vaccines should be developed, and inactivated TB vaccines may also be evaluated in this population. As live attenuated vaccines are being developed for infants, it will be important to know the safety, immunogenicity, and efficacy of these vaccines in infants with HIV on ART.
4. What are the trial design considerations of TB vaccine trials that include people with HIV?
Including people with HIV in TB vaccine trials raises many important design issues that should be considered. These trial design considerations can be divided into 8 sub-considerations: 1) participant characteristics; 2) standard of care (SOC); 3) eligibility criteria; 4) efficacy endpoints; 5) statistics; 6) ethics; 7) regulatory policies; and 8) community involvement. We have provided context and consensus statements for each sub-consideration below.
4.1: When should people with HIV be included in TB vaccine trials?
Context: People with HIV are at high risk of TB disease and would benefit from participating in TB vaccine trials as soon as safely possible to minimize the time to accessing effective TB vaccines that come to market.
Consensus statement: Among adults, adolescents, children, and infants with HIV:
Subunit, viral vectored, inactivated, and novel mRNA or DNA TB vaccines, once developed, may be evaluated in Phase 1b trials, depending on the preclinical safety profile of the candidate vaccine, and then in Phase 2, Phase 3 and post-licensure trials.
BCG and new live attenuated vaccines may be evaluated in Phase 2, Phase 3, and post-licensure trials, depending on CD4 count and viral load and if there is prospect for more benefit than harm. That is, the safety and efficacy signal in HIV-negative persons supports further development.
Pregnant women with HIV on ART:
May be included in Phase 2, Phase 3, and post-licensure trials of subunit, viral vectored, and inactivated vaccines.
Should not be considered for planned trials of BCG and new live attenuated vaccines, as WHO does not recommend BCG for pregnant women.
4.2: What should the SOC be for people with HIV in TB vaccine trials?
Context: An effective TB vaccine for people with HIV would complement existing tools for TB prevention in people with HIV, which includes early disease detection, prompt diagnosis and treatment, infection prevention and control, and TPT.
TPT is the WHO standard of prevention for people with HIV1. Isoniazid preventive treatment in conjunction with ART is more effective in reducing the risk of TB than ART alone38. An extended duration of isoniazid TPT was found to be equally effective as short-term rifamycin and isoniazid-based therapy in reducing TB risk in people with HIV39. As the combined effect of TPT with immune modulation is greater than either intervention alone, it is reasonable to assume that TPT with TB vaccines may have a synergistic effect on reducing the risk of developing TB disease. However, offering TPT to eligible participants with HIV in TB vaccine trials may reduce the apparent effectiveness of TB vaccines. This confounder is not unlike offering pre-exposure prophylaxis (PrEP) to participants in HIV vaccine clinical trials; ethically, it is the right thing to do but does reduce the power to observe potential vaccine efficacy. Thus, next generation HIV vaccine (or other preventative strategies such as monoclonal antibodies) trials are being designed to allow for a lower incidence due to PrEP uptake40.
Consensus statement: All people with HIV participating in TB vaccine trials must be on ART. As WHO recommends TPT as SOC for people with HIV regardless of Mtb infection status, TB vaccine trial participants with HIV (on ART), regardless of age, Mtb infection status, phase of trial (1–3) or mechanism of action (POI, POD, POR), should either previously have completed a course of TPT prior to enrolment or be offered TPT during the study if they previously have not completed a course of TPT and have no evidence of active TB disease. In trials of live attenuated TB vaccines, TPT should not be provided in the trial, as TPT may reduce the activity of live attenuated TB vaccines. Persons eligible for TPT who have not previously taken TPT should be advised to complete a course of TPT prior to enrolling in the trial.
4.3: What are the HIV-specific eligibility criteria?
Context: As CD4 + T-cell count and viral load are predictive of developing opportunistic infections, survival, and vaccine responses, these clinical characteristics should be included as eligibility criteria in TB vaccine trials that include participants with HIV. People with HIV receiving ART should therefore only be considered for inclusion in TB vaccine trials if viremia and CD4 + T-cell counts meet pre-specified thresholds.
Consensus statement: Eligibility criteria for people with HIV on ART differ depending on CD4 + T-cell count. Participants with HIV with CD4 + T-cell counts < 100 cells/mm3 or HIV RNA > 200 copies/mL:
Should be excluded from trials of BCG and live attenuated vaccines.
May be included in Phase 1b/2 trials of subunit, viral vectored and inactivated TB vaccines.
May be included in Phase 3 trials if vaccines are shown to be safe and immunogenic in Phase 2 trials.
Participants with HIV with CD4 + T-cell counts ≥ 100 cells/mm3 or HIV RNA < 200 copies/mL may be included in:
Phase 1b/2 trials of subunit, viral vectored, and inactivated TB vaccines
Phase 2 trials of live attenuated TB vaccines
Phase 3 trials of subunit, viral vectored, inactivated, and live attenuated TB vaccines, if shown to be safe and immunogenic in Phase 2 trials.
4.4: What are the HIV-specific efficacy endpoints for people with HIV?
Context: TB among people with HIV is often paucibacillary, extrapulmonary or subclinical, particularly among those with marked immunosuppression41,42. POI vaccine trials in infants, uninfected adolescents or adults evaluate Mtb infection as the endpoint. The gold standard diagnostic for Mtb infection is the interferon gamma release assay (IGRA), which measures cytokine production from Mtb antigen stimulated blood cells. Also, it has been shown that higher IGRA levels or sustained conversion predicts a greater risk of TB disease progression. Whether this holds true for people with HIV is currently unknown, as is how accurate IGRA is in this population. POD vaccine trials typically evaluate clinical, bacteriologically confirmed, pulmonary TB disease as a highly specific endpoint using solid and liquid culture methods and nucleic acid amplification assays.
Subclinical TB occurs frequently in people with HIV and may have a role in Mtb transmission. A benefit of including subclinical TB as an endpoint in POD/POR/therapeutic vaccine studies is that it may decrease the sample size and reduce the duration of follow-up, as subclinical TB would contribute to the number of endpoints and occurs earlier than clinical TB disease. The decrease in sample size, however, assumes that the vaccine will be equally efficacious at preventing clinical and subclinical TB. It’s unclear whether prevention of subclinical TB should be a priority for POD, POR and therapeutic TB vaccines, for the following reasons: preventing subclinical TB would be a higher bar for the vaccine to achieve; the evidence that subclinical TB substantially contributes to TB transmission is still circumstantial; identifying and treating subclinical TB disease may compromise the ability to show efficacy against clinical TB.
Both POR and therapeutic TB vaccine trials evaluate clinical, bacteriologically confirmed, recurrent pulmonary TB disease as a highly specific endpoint using solid or liquid sputum culture; therapeutic trials additionally consider treatment failure and TB-related deaths as unfavourable outcomes in a trial. Isolates of Mtb should undergo whole genome sequencing to characterize recurrent TB as relapse or reinfection TB.
Consensus statement: Efficacy endpoints for HIV-infected participants overall should be the same as for HIV-uninfected participants in POI, POD, POR and therapeutic TB vaccine trials. As paucibacillary, extrapulmonary or subclinical TB occurs more commonly in people with HIV, consideration should be given to also include these as endpoints in TB vaccine trials among people with HIV. So as not to compromise evaluation of efficacy in preventing clinical (symptomatic) TB disease, subclinical TB should ideally only be assessed at the end of follow-up. As sustained Mtb infection is used as an endpoint in POI trials, the risk of TB among people with HIV with sustained TB infection should be established.
4.5: What are the trial design and statistical considerations?
Context: Statistical considerations for TB vaccine trials involving people with HIV include comparator arms, immune-bridging, and sample size. TPT history, participant preferences and values, and local policy should also be considered when designing POD TB vaccine efficacy trials.
Consensus statements: As a comparator arm, placebo gives the best chance of minimizing bias and is the preferred choice, except in infants for whom BCG is licensed and has shown efficacy. Therefore, a placebo should not be used in BCG-naïve infants who are well controlled on ART; rather, BCG should serve as the SOC comparator. Similarly, the comparator arms for testing safety and efficacy of live attenuated vaccines in older children, adolescents and adults who are well controlled on ART should include BCG revaccination, in addition to placebo, to enable comparison with BCG if a new vaccine is shown to be efficacious in this age group.
We recommend using immune-bridging studies, which measure participant immune responses to vaccines rather than waiting for efficacy endpoints, for people with HIV if a correlate of protection (CoP) has been identified and people with HIV are not a sufficiently large subgroup in Phase 3 trials to permit precise estimation of efficacy.
4.6: What are the ethical considerations?
Context: People with HIV have a more urgent need for TB vaccines than the general population given their significantly higher risks of developing TB disease, drug-drug interactions, and poorer TB treatment outcomes1–3. Consequently, delays in developing an effective TB vaccine for people with HIV would have greater individual-level consequences than for the general population. Excluding people with HIV from TB vaccine trials would worsen existing health disparities. The differentially higher burden of TB among people with HIV justifies inclusion of people with HIV in TB vaccine trials with some degree of greater in-trial risk compared to participants from the lower urgency general population.
Consensus statement: An equity-oriented research agenda that seeks to reduce disparities between people with HIV and the general population should be adopted. The timing of when to include people with HIV in TB vaccine trials should be based on consideration of risks (safety) versus the need to reduce the “time-to-evidence” for people with HIV.
4.7: What are the regulatory considerations?
Context: In order to increase enrolment of underrepresented populations, including people with HIV, in later phase clinical trials, sponsors can follow the U.S. FDA Guidance for Industry43. Sponsors developing a TB vaccine are encouraged to submit an Investigational New Drug Application even if the U.S. market for that vaccine is limited and the primary target population is outside of the U.S.44,45. Expedited program designations are available to facilitate development of qualifying TB vaccines for people with HIV46. TB is on the list of qualifying tropical diseases eligible for a Tropical Disease Priority Review Voucher, which includes TB vaccines developed for people with HIV47.
Consensus statement: Communication with regulatory authorities should occur early and throughout the development process.
4.8: How should community be involved?
Context: In the past few years, HIV vaccine efficacy trial design has been modified to account for volunteer willingness to take PrEP40,48. This newer trial design was implemented after extensive community engagement and deliberations with community advisory boards (CABs) and other local leaders49. This type of creative next-generation trial design can be applied to the TB vaccine field to ensure people with HIV are included safely. Additionally, CABs and other community stakeholders significantly enhance enrolment and retention of participants in clinical trials, especially in underserved populations50,51.
Consensus statement: Community stakeholders of people with HIV should be engaged early in the process to ensure best outcomes and to provide input into study design, trial conduct, and results dissemination.