Prioritizing COVID-19 Clinical Research Needs in Low-Resource Settings

Since the beginning of the COVID-19 pandemic, there has been a limited focus on the needs of low-resource settings, including of clinical research priorities. The “global” research response has largely been conducted by stakeholders from or based in the Global North in response to their own needs.

With few exceptions, funding and prioritization of the clinical research priorities in low-resource settings has been inadequate.

Important work has been done by other organizations to identify global or region-specific research priorities, including by the World Health Organization, the Africa CDC, the African Academy of Sciences, and others.

One of the challenges has been to reduce longer priority lists or less detailed priority areas to just a few specific “top” priorities. Several working groups of topic-specific experts in the COVID-19 Clinical Research Coalition have worked together to identify the top 5 research priorities in their respective domains, from clinical epidemiology to virology, immunology and diagnostics.

Working group members undertook a collaborative exercise, referring to existing research priority lists (see links above) and brainstorming, holding consensus-based meetings, and in some cases running multi-language surveys and using a Delphi-like process to finalize lists of questions that had not yet been adequately addressed in current research, as well as questions for which available evidence was insufficient. In this exercise, coalition members adopted a bottom-up approach to identify the challenges most relevant in low-resource settings without being regional-specific.

Clinical Epidemiology Working Group​

  1. What signs and symptoms can confirm the clinical diagnosis of COVID-19? 
  2. What clinical findings (signs, symptoms, biomarkers, and imaging) are associated with a worse prognosis in COVID-19? ​
  3. What is the best strategy to achieve treatment goals in patients with non-communicable diseases (NCDs) during the COVID-19 pandemic? ​
  4. What are the short, mid-, and long-term post-infectious sequelae of COVID-19? ​
  5. What is the COVID-19 Infection Fatality Rate in low and middle countries, including stratification by age? ​
  6. What is the excess mortality of non-COVID-19 in low- and middle-income countries (LMIC) during the pandemic? ​
QuestionPopulation/Patient/ProblemExposure(s)/Intervention(s)Comparison(s)Outcome(s)
1. What clinical findings (signs, symptoms, biomarkers and imaging) are associated with a worse prognosis in COVID-19?Outpatients with clinical suspicion of COVID-19

Mild to moderate COVID-19
Clinical findings: e.g. fever, headache, cough, dyspnea, chest pain, abdominal pain, diarrhea, pulse oximetry.

Vital signs: e.g. respiratory rate, heart rate, blood pressure.

Markers of comorbidities: e.g HT, DM, hyperglycemia.

Biomarkers: e.g. white-cell count.

Imaging findings (CT vs radiograph): ground-glass opacity (GGO), local patchy shadowing, bilateral patchy shadowing, interstitial abnormalities.
Absence of findings.

Number/combination of findings
Admission to hospital (and associated clinical events during hospitalization)

Progression to severe COVID-19
Patients admitted to hospital with clinical suspicion of COVID-19Clinical findings: e.g. fever, headache, cough, dyspnea, chest pain, abdominal pain, diarrhea.

Biomarkers: e.g. albumin, ALT, AST, creatinine, white-cell count, consider: ferritin, troponin, BNP, procalcitonin.

Imaging findings (CT vs radiograph): ground-glass opacity (GGO), local patchy shadowing, bilateral patchy shadowing, interstitial abnormalities.
Absence of findings.

Number/combination of findings
Any of the following:

ICU admission

Mechanical ventilation

In-hospital death

Re-admission to hospital

Death (30/ 90 day)

Quality of life (90 day)
2. What signs and symptoms could confirm the clinical diagnosis of COVID-19?Outpatients with clinical suspicion of COVID-19History of (home, social) contact with a confirmed/suspected case of SARS-CoV-2 infection.

Vital signs: e.g. respiratory rate, heart rate, blood pressure.

Clinical findings: e.g. fever, headache, cough, dyspnea, chest pain, abdominal pain, diarrhea, pulse oximetry
Absence of findings

Number/combination of findings

Accepted gold standard (e.g. imaging findings + clinical diagnosis + RT-PCR)
Laboratory diagnosis of COVID-19 (sensitivity, specificity)
3. What is the best strategy to achieve treatment goals in patients with NCDs during the pandemic?Patients with NCDs

*NCDs including hypertension, diabetes, hypercholesterolemia.
Educational strategies: printed materials, handouts, online campaigns, text messages.

Health services interventions: follow up-appointments, telehealth, incentives for improving adherence/ achieving treatment goals.

Patients with NCDs with multidisciplinary team approach to treatment and targeted treatment for comorbidities.
No interventions

Combination of different interventions.

Patients with NCDs receiving standard of care at a health facility
Achieving treatment goals in the included health conditions (e.g. use of clinically meaningful endpoints, blood pressure control, glycemic control)
Patients with NCDs and probable/confirmed COVID-19 infection and admittedEducational strategies: printed materials, handouts, online campaigns, text messages.

Health services interventions: follow up-appointments, telehealth, incentives for improving adherence/ achieving treatment goals.

Patients with COVID-19 and NCDs with multidisciplinary team approach to treatment and targeted treatment for comorbidities.
No interventions

Combination of different interventions.

Patients with COVID-19 and NCDs receiving standard of care at a health facility.
Achieving treatment goals in the included health conditions (e.g. use of clinically meaningful endpoints, blood pressure control, glycemic control)
4. What is the COVID-19 Infection Fatality Rate in low and middle countries +/- stratified by age?Reported or confirmed cases in the area under study.

Patients with probable/ confirmed COVID-19 infection

Population based cohort study of patients with the standardized definition of exposure
Age different categories and confounder variables such as sex, comorbidities, BMI, smoking, alcoholism, ICU admission.Age different categoriesDeath:

In hospital
30 day
90 day
5. What is the excess mortality non-COVID-19 in LMIC during the pandemic?Global or regional population under studyNon-COVID deaths during the pandemic in LMIC countries

Overall mortality during the pandemic
Non-COVID deaths during the pandemic in high -income countries

Overall mortality during previous periods (historical comparator)
Excess of non-COVID deaths during the observation period

Maternal, Newborn and Child Health Working Group​

​Access to healthcare, treatment and vaccination trials for women and children during the COVID-19 pandemic​

  • What are the effects of the pandemic response on availability of and access to maternal, sexual and reproductive health, child and adolescent health services?​
  • What is the safety and efficacy of treatment for SARS-COV2 in pregnant women and children? What are the ethical considerations that would enable women and children to be included in COVID19 treatment and vaccination clinical trials?​
  • Are women in LMICs able to access antenatal care? If access is reduced, what are the main barriers and how can they be overcome? ​

Direct effects of the SARS-CoV-2 virus on pregnant and breastfeeding women and children​

  • Are pregnant women with COVID-19 at increased risk of hospitalisation, intensive care unit admission and death compared to non-pregnant women? What is the immunopathological basis for these outcomes?​
  • What is the pathophysiology of severe COVID-19 infection in children?​
  • What is the immunopathological mechanism of PIMS-TS?​

Indirect effects of the COVID-19 pandemic on pregnant and breastfeeding women and children​

  • What is the effect of the pandemic on maternal and child mental health? ​
  • What are the main social drivers in the rise in sexual and gender-based violence during the COVID-19 pandemic?​
  • What are the long-term effects of the COVID-19 restrictions on early childhood development?​
  • How has the disruption of routine childhood disease prevention and surveillance affected future rates of vaccine preventable diseases?​

Transmission of the SARS-CoV-2 virus and protection from infection​

  • Do antibodies against the SARS-CoV-2 virus expressed in breastmilk confer protective immunity against the SARS-CoV-2 virus in infants?​
  • What are the neurodevelopmental effects of SARS-CoV-2 exposure in utero?​
  • What proportion of SARS-CoV-2 community transmission is by children?​

Social Science Working Group​

Political economy​

  • How are COVID-19 public health decisions and the trajectory of the epidemic affected by each country’s political-economic context?​​
  • How are political actors using COVID-19 to leverage political agendas? How has the COVID-19 pandemic and response been shaped by political priorities? What reactions have we seen to this?​​
  • How does the political-economic context affect public trust in the response? How does this impact uptake of public health guidance or trust in health and medical providers?

Clinical trials and vaccine deployment​

  • How can governments and COVID-19 country coordinating bodies improve public trust, acceptability, effectiveness, and uptake of COVID-19 vaccines and therapeutics? How have rumors and misinformation affected these processes? ​​
  • What forms of community engagement have been ongoing in COVID-19 clinical trials? How might community engagement be increased or systematized for COVID-19 clinical trials?​​
  • With increasing nationalism, how might countries in the Global South access COVID-19 vaccines and therapeutics once available? ​​
  • How are issues of social justice reflected in competition over and access to COVID-19 therapeutics and vaccines?​

Transnationalism​

  • How are borders being settled or re-affirmed conceptually? What are challenges related to transnational or regional collaboration and how is this affected by the hardening of national borders?​​
  • How are transnational populations (border communities, transnational migrants) affected by dynamics of the pandemic, nationalism, and national-level public health response? How are transnational populations affected by and represented in COVID-19 policymaking?​

Preventative and health-seeking behavior

  • How does trust in various public health actors affect health-seeking behavior? How might multiple uncertainties around the pandemic, including prevention and treatment, affect how and when individuals engage in preventative or treatment-seeking behavior?​​
  • How do individuals understand the social construction of risk and how does this drive when and how to seek health care for COVID-19? How does the general population perceive, understand, construct, COVID-19 risk and how does it affect their practices?​​
  • How is COVID-19 stigma and other forms of social stigma affecting health-seeking behavior?​​
  • How are vulnerabilities and social difference manifesting in health care access and ability to engage in health-seeking behavior?​​
  • What are the secondary health impacts of COVID-19? How is a vertical COVID-19 response affecting health-seeking behavior for other non-COVID medical needs?​

Virology, Immunology, and Diagnostics Working Group​

  1. What is the feasibility and performance of “alternative” samples (nasal/saliva/oropharyngeal) for self-administered collection? ​
  2. What is the impact on serological test performance of different disease backgrounds (e.g., malaria, HIV, TB)? ​
  3. What is the role of antigen tests in different populations and settings? ​
  4. Are PCR testing results (e.g., cycle threshold) associated with infectivity? ​
  5. What are the various approaches to setting up biobanks of COVID-19 samples? ​
QuestionPopulation/Patient/ProblemExposure(s)/Intervention(s)Comparison(s)Outcome(s)
1. What is the performance of serological tests in different populations (malaria, HIV, TB) and settings)Population: Individuals presenting with signs and symptoms of COVID-19 and having comorbid conditions (TB and HIV)
Problem: Immune supressing conditions, eg TB/HIV are likely to affect the performance of COVID-19 diagnostics tests
- Clinical diagnosis of COVID-19
- RT-PCR testing
- Serological COVID testing
Individuals with no immune suppressing comorbid conditions- False negative COVID 19 test
- Progression to critical/severe disease
Population: Individuals from Malaria holoendeic areas presenting with signs and symptoms of COVID-19
Problem: Performance of the COVID-19 tests is likely to be lower in malaria holoendemic regions
- Clinical diagnosis of COVID 19
- RT-PCR testing
- Serological COVID testing
Individuals from non malaria holoendemic regions
- False negative COVID 19 test
Progression to critical/severe disease
2. What are the various approaches to setting up biobanks of COVID-19 samples
Population: COVID-19 patients with varrying grades of disease severity
Problem: To inform future research on COVID and any other outbreaks, there is a need for eastablishment of biobanks with high quality and well annotated samples. Approaches relevant to COVID to inform this are however missing
Consultative process with laboratory & clinical experts to inform development of guidelines
Routine/non COVID- 19 biobanking guidelines
COVID 19 specific biobanking guidelines
3. What is the best way to use PCR testing methods to determine infectivity?Population: COVID 19 patients diagnosed on basis of RT-PCR and contacts of COVID 19 patients
Problem: There still exists gaps in understanding the level of infectiousness of COVID 19 patients diagnosed by RT-PCR and yet such information would inform public health decisions e.g. when to return to work, who to isolate, contact tracing among others
- RT-PCR testing and analysis of Ct values at different days of symptom onset
- Culture
COVID 19 patients at various days since contact or symptom onset
- Infectiousness
- Culture result
4. What is the feasibility and performance of self-administered nasal/oropharyngeal swab collection?Population: Individuals with symptoms of COVID
Problem: Current COVID sample collection procedures necessitate a health worker to collect the sample from the patient. This however leads to exposure of the health workers and indeed some of them have been infected as a result. Furthermore, this leads to PPE related costs.
Self administered sample collection (self-swab)
Healthworker collected swabs
Developed self administered sample collection protocols