Ongoing Studies – INA-RESPOND

InVITE Study

By: Eka Windari R., Nur Latifah Hanum, Restu Amalia Mukti

The InVITE serum specimens from the main study visits 1, 2, and 3, as well as symptomatic visits, are currently undergoing analysis at the Central Laboratory, NIH, US. Additionally, RNA extracted from midturbinate swabs collected in UTM during symptomatic visits will be shipped alongside serum specimens from extension visits 4 and 5. This shipment is planned for June 2025, with the analysis of all specimens expected to be completed this year. To facilitate this process, the INA-RESPOND team is preparing to submit a draft of a new Material Transfer Agreement (MTA) to the MTA Committee via their website. Simultaneously, the team is also preparing for the Site Close-out Visit (SCV), scheduled for February 2025, after receiving SCV approval from the InVITE Global team.

The InVITE Publication Committee holds routine meetings to discuss ongoing manuscript development and review concept plans related to InVITE data and specimen usage. Recently, a new concept plan from the Kirby Institute, UNSW, was submitted to the committee, proposing an assessment of the neutralization capacity of sera from InVITE participants.

Given the evolution of SARS-CoV-2, with mutations in its Spike protein affecting transmissibility and immune evasion, different countries have experienced unique variant distributions due to varying immunity levels. Variants achieve dominance through transmission advantages and immune escape, while factors such as vaccine type, dosage, and time since vaccination influence population-level neutralization responses, which broaden over time.

The submitter highlighted that while global data on immune responses to variants exist, data from countries participating in the InVITE study remain limited. This sub-study aims to fill this gap, con-tributing to future pandemic preparedness and vaccine accessibility planning. Specifically, it will examine post-vaccination neutralization capacity, its duration of effectiveness, and how vaccine plat-forms and natural infection influence neutralization responses across different variants.

The sub-study will utilize a highly sensitive live-cell serology assay to evaluate the breadth of neutralization across SARS-CoV-2 variants representing the global pandemic trajectory. Each pandemic year will be covered by one representative variant, including Ancestral (2020), Delta (2021), BA.5 (2022), XBB.1.5 (2023), and JN.1 (2024). This approach ensures a comprehensive assessment of neutralization capacity across key viral variants and different COVID-19 vaccines, providing critical insights into real-world immune responses over time.

While the InVITE Publication Committee will decide on the approval of the concept plan, this potential sub-study has already been communicated to INA-RESPOND via email. Key concerns raised include the requirement for Local Ethics Committee approval for a new sub-study and the shipment of sera specimens from Visits 1–5 to the Kirby Institute in Australia. The MTA procedure will be further discussed with the MTA Committee once all InVITE specimens have been sent to the Central Laboratory.

PROACTIVE Study

By: Eka Windari R., Nur Latifah Hanum, Restu Amalia Mukti

The Impact of the COVID-19 Pandemic on the INA-PROACTIVE Study

The INA-PROACTIVE (INA-104) study, which concluded in 2023, is now in the final stages of preparing its report for the Ethics Committee. As part of this final report, the team has documented a temporary suspension of the study due to the impact of the COVID-19 pandemic, particularly during its initial phase in 2020. This unforeseen disruption posed significant challenges but also provided valuable lessons for future research. The experience underscored the importance of adaptive study designs, contingency planning, and flexible research methodologies to ensure continuity in the face of global health crises.

Following the first reported COVID-19 cases in Indonesia on March 2, 2020, INA-RESPOND issued its first memorandum on March 16, 2020, announcing the temporary suspension of recruitment and follow-up activities. The memo outlined that, in response to the COVID-19 pandemic and in accordance with the Indonesian Minister of Health’s Decree No. HK.01.07/Menkes/169/2020—which designated referral hospitals for managing emerging infectious diseases—all INA-RESPOND research sites were instructed to pause subject recruitment and follow-up visits from March 16 to March 28, 2020.

A second memo was issued on April 2, 2020, extending the suspension period from March 28 to April 11, 2020. As the pandemic worsened, a third memo was released on April 13, 2020, providing an updated notification that the suspension of subject recruitment and follow-up visits would remain in effect indefinitely until further notice. The decision was made to protect both the study team and participants while aligning with government policies to prevent transmission at a time when diagnostic tools and effective treatments were not yet available.

During the temporary suspension, Research Assistants (RAs) focused on completing pending tasks, such as updating research data, organizing the site regulatory binder, and conducting refresher training on study procedures. As health protocols for staff and service processes were gradually implemented across hospital sites, INA-RESPOND decided to allow study visits to resume starting September 1, 2020. However, if any site encountered conditions that posed a risk to the safety of participants or the research team, they were allowed to pause follow-up activities as long as they informed the INA-RESPOND Secretariat in advance.

For subjects whose visit schedules were nearing the end of the window period during the temporary suspension, visits were still conducted when possible to minimize missed visits due to subject absences. This approach helped ensure strong subject retention throughout the study. Additionally, RAs maintained regular communication with participants through WhatsApp messages, phone calls, and tracking their involvement in HIV support groups when direct communication failed. These efforts maximized the continuity of participant engagement in the study.

One of the key challenges encountered was the unavailability of HIV-Viral Load (HIV-VL) cartridges, as suppliers reallocated production to meet the urgent demand for SARS-CoV-2 cartridges. As a result, the protocol team decided to allow subjects to continue their scheduled study visits while postponing VL testing. Specimens were still collected and stored to ensure testing could be completed once cartridges became available. This delay impacted data completeness, as VL results could not be documented immediately after follow-up visits, requiring additional time for testing. To maintain data integrity, sites completed and uploaded case report forms (CRFs) with available information, while VL results were updated later in the On-Site Data Clarification Forms (ODCFs) within the Electronic Data Management System (EDMS). RAs also documented this delay by submitting protocol deviation forms in Log 1300, using minor protocol code 39, as VL testing exceeded the required 24-hour timeline.

Additionally, RAs were instructed to document any participant diagnosed with COVID-19 in the Case Report Form (CRF; Log 200) and report it as an Important Medical Event (IME). During the study period, a total of 138 IMEs were reported. Notably, in the INA-PROACTIVE study, COVID-19 emerged as the leading contributor to non-AIDS-related mortality, accounting for 10 out of 62 non-AIDS-related deaths (16.1%) among adult participants. These findings provide crucial insights for researchers, clinicians, and policymakers, emphasizing the significant impact of COVID-19 on individuals living with HIV.

In summary, the impact of COVID-19 on the INA-PROACTIVE study was significant. Lockdowns and social distancing measures challenged in-person visits, resulting in lower enrolment and follow-up rates. The pandemic also raised concerns about study integrity, as interruptions in data collection and deviations from original protocols threatened the reliability of study outcomes. Reallocating healthcare and laboratory resources toward the COVID-19 response also created barriers to conducting the study as planned.

Despite these challenges, the INA-PROACTIVE study team successfully adapted its research procedures to ensure study continuity while maintaining data quality. This experience highlights the importance of proactive planning and flexibility in long-term observational studies, especially when faced with unforeseen global disruptions like the COVID-19 pandemic. Looking ahead, telemedicine and remote monitoring could serve as alternative solutions, allowing researchers to conduct virtual visits, collect data electronically, and reduce in-person interactions. Additionally, flexible study protocols, such as decentralized and adaptive designs, can help mitigate disruptions while ensuring patient safety.