Science AI Journal
Medicine · Research topic

Open research questions in SARS-CoV-2 and COVID-19 Research

72 unresolved questions extracted from the limitations and future-work sections of 729 SARS-CoV-2 and COVID-19 Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • [116 words] Few studies have characterized immune correlates of SARS-CoV-2 infection risk in children, particularly those with hybrid immunity from vaccination and prior infection.

    Immune correlates of risk for SARS-CoV-2 infection in children: a prospective, community-based cohort study · 2026 · DOI

  • ABSTRACT GC content—the proportion of guanine and cytosine nucleotides—varies widely among organisms and viruses.

    GC content mismatch of transgene destabilizes RNA virus genomes · 2026 · DOI

  • Although its role in cellular genomes has been extensively studied, the functional significance of GC content in viral genomes remains poorly understood.

    GC content mismatch of transgene destabilizes RNA virus genomes · 2026 · DOI

  • The association between COVID-19 vaccination and Guillain-Barre syndrome (GBS) has been previously investigated with inconsistent results, largely due to limited data and lack of concurrent controls.

    COVID-19 mRNA Vaccination Reduces Guillain-Barre Syndrome Risk: Evidence from a Large Longitudinal Cohort Study · 2026 · DOI

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers expression of endogenous retroviruses (ERVs), but whether this persists during coronavirus disease 2019 (COVID-19) and contributes to disease severity has not been well characterized.

    Bulk and single-cell transcriptomics reveal elevated endogenous retrovirus expression linked to immunopathology in severe COVID-19. · 2026 · DOI

  • Although we have identified and adjusted for many baseline confounders, cohort assignment was not randomized, and residual confound- ing may remain, as is inherent to observational study designs. For instance, vaccinated individ- uals may engage in other behaviors associated with a healthier lifestyle, such as more frequent exercise, contributing to their lower rates of hospitalization with COVID-19 and this may not be addressed with the available covariates. Also, the study population only includes indi- viduals engaged with the healthcare system, possibly excluding others due to barriers such as trust, socioeconomic status, or accessibility. The outcome definition of hospitalization with COVID-19 partially mitigates this limitation, as severe outcomes are less influenced by vari- ation in healthcare-seeking behavior. Although the study design requires that vaccinated indi- viduals remain event-free for 7 days following vaccination, the use of a symmetric study design among the unvaccinated cohorts minimizes the introduction of bias between cohorts. As with all claims and/or EHR data, vaccina- tion status may be incompletely captured, which could have led to bias toward the null hypoth- esis and resulted in underestimation of true aVE. In addition, outcomes may be underestimated if people avoid obtaining medical care. While treatment avoidance is possible in both vacci- nated and unvaccinated individuals, patients who avoid vaccination may be more likely to avoid other medically-necessary care. This differ- ence in healthcare seeking behavior would also bias towards underestimating aVE Misclassifica- tion of both exposure and outcomes is also pos- sible, as diagnostic and procedural codes used to define vaccination and COVID-19-related hospi- talization may be subject to coding errors. How- ever, validation studies suggest that outcome misclassification is likely limited; for example, Kadri et al. reported that the ICD-10-CM code U07.1 for COVID-19 had a positive predictive value of approximately 98% when compared with clinical documentation and laboratory- confirmed infection [20]. A further limitation is that for some patients COVID-19 may be an incidental diagnosis that is captured as part of a hospitalization for an unrelated health event. While this is possible, the weighting process should ensure that the odds of an unrelated hospitalization are similar between cases and controls. Therefore, while this may lead to an overestimate of the frequency of COVID-19-related hospitalizations it should not bias the aVE results. Furthermore, the low frequency of hospitalizations, particularly in the subgroup analysis, resulted in large confidence intervals in adjusted aVE. Additional analyses with data from the full season that allows for the capture of more events over a longer follow-up time may help assess the durability of vaccine effectiveness and improve confidence in these findings. Additionally, these data sources may not fully capture all hospitalizations, particularly among populations with limited or fragmented access to care, such as uninsured individuals, underrep- resented groups, or those receiving care outside the insurance network. The patient selection also excluded patients based on receipt of immu- nomodulators used to treat COVID-19; however, this approach likely excluded individuals who received these medications for non-COVID-19 indications. This may affect generalizability and introduce selection bias, though the exclusions were applied to both cases and controls.

    Interim Effectiveness of 2025–2026 mRNA-1283 and BNT162b2 COVID-19 Vaccines Against COVID-19-Related Outcomes Among Adults Aged ≥ 65 Years in the United States · 2026 · DOI

  • Immunocompromised individuals rely not only on direct vaccination but also on herd immunity for protection. High vaccination coverage among caregivers, household members, and the general population is critical in reducing the risk of exposure. This underscores the need for strong public health initiatives that promote widespread immunization, particularly during outbreaks of vaccine-preventable diseases such as influenza, measles, and COVID-19. protocols immunization Moving forward, continued research is necessary to optimize for immunocompromised individuals. Clinical trials should include more immunosuppressed participants to better understand vaccine efficacy and safety in these in immunology and vaccine technology, including next-generation vaccines designed to elicit stronger immune responses in immunocompromised patients, hold promise for improving protection. populations. Moreover, advances REFERENCES 1. Akkaya, M., Kwak, K., & Pierce, S. K. (2020). B cell memory and plasma cell formation in the context of chronic antigen stimulation: Lessons from autoimmunity and infection. Frontiers in Immunology, 11, 621222. 2. Apostolidis, S. A., Kakara, M., Painter, M. M., et al. (2021). Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nature Medicine, 27(11), 1990-2001. 3. Bastard, P., Rosen, L. B., Zhang, Q., et al. (2020). Auto-antibodies against type I IFNs in patients with Science, 370(6515), eabd4585. life-threatening COVID-19. 4. Boyarsky, B. J., Werbel, W. A., Avery, R. K., et al. (2021). Immunogenicity of a single dose of SARS- CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA, 325(17), 1784-1786. 5. Centers for Disease Control and Prevention (CDC). (2022). Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Retrieved from https://www.cdc.gov/coronavirus/2019- ncov/vaccines/recommendations/immuno.html 6. Diaz Granados, C. A., Dunning, A. J., Kimmel, M., et al. (2014). Efficacy of high-dose versus standard-dose influenza vaccine in older adults. New England Journal of Medicine, 371(7), 635- 645. 7. O’Brien, M. P., Forleo-Neto, E., Musser, B. J., et al. (2022). Subcutaneous REGEN-COV antibody combination to prevent COVID-19. New England Journal of Medicine, 385(13), 1184-1195.

    <b>Navigating the Complexities of Vaccination in Immunocompromised Patients: Balancing Protection and Risk</b> · 2026 · DOI

  • Thus, the results of our study fill a critical gap in knowledge regarding the poten- tial benefits of the omicron variant-adapted seasonal COVID-19 vaccine and demonstrate that it may not only continue to protect against severe COVID-19 outcomes, but also against PCC. Although a large body of literature exists on the protective effect of the pandemic-era vaccines in preventing PCC [7, 16], data on the post-pandemic variant-adapted seasonal vac- cines is scarce.

    Effectiveness of seasonal mRNA COVID-19 vaccination against post COVID-19 condition between July 2023 and September 2024 among adults aged ≥ 60 years in Germany: a population-based cohort study · 2026 · DOI

  • Collectively, our findings demonstrate that Anx5 directly engages both Spike-RBD and ACE2, inhibits SARS-CoV-2 pseudoviral entry and reduces viral burden while enhancing survival of infected mammalian cells, supporting further investigation of Anx5 as a multi-functional anti-SARS-CoV-2 therapeutic.

    Dual engagement of Spike and ACE2 by annexin A5 contributes to pleiotropic SARS-CoV-2 inhibition · 2026 · DOI

  • Although the N protein is extensively phosphorylated within its central Ser/Arg-rich region by glycogen synthase kinase-3 (GSK-3), the functional significance and dynamic regulation of its phosphorylation state during the viral life cycle remain incompletely understood.

    <b>Dynamic </b><b>Phosphorylation of the SARS-CoV-2 Nucleocapsid Protein Regulates Viral Particle Assembly</b> · 2026 · DOI

  • Introduction Post-COVID syndrome represents a major global health challenge which is characterized by immune dysregulation, although many aspects of the immune response remain incompletely understood, particularly the antibody response and the role of the complement system.

    Increased anti-nucleocapsid secretory IgA and consumption of complement component 3 in post-COVID syndrome patients · 2026 · DOI

  • Fundamental concepts and current challenges In the context of advancing mRNA vaccine strategies for viral immunity, several key challenges and future directions emerge from this synthesis. As summarized above, existing mRNA vaccines still encounter challenges, such as poor stability, which requires ultra-low temperature storage and transportation (Yang et al., 2023). This drawback limits their application in regions with limited resources. The delivery efficiency is still not optimal, as a substantial amount of mRNA is retained and degraded within endosomes, which impairs expression and immune activation. This can lead to local or systemic inflammatory reactions, such as hypersensitivity reactions and myocarditis (Jaggers and Wolfson, 2023; Oster et al., 2022).

    mRNA vaccines against viral pathogens: molecular design, delivery systems, and clinical applications · 2026 · DOI

  • However, a limitation of this study is that sequencing was restricted to samples with Ct values ≤ 32, excluding samples with low viral loads, which may have impacted the accuracy of our lineage frequency estimates.

    Comprehensive whole-genome characterization of SARS-CoV-2 strains in Jining China 2024–2025 · 2026 · DOI

  • According to the WHO, COVID-19 vaccination helps to reduce the number of deaths due to the disease, particularly in immunocompetent individuals. However, crucial knowledge gaps exist in evaluating the same in a heterogeneous population with a spectrum of host immune responses. Some of the challenges are discussed below: 1. At least one dose of the COVID-19 vaccine has been recommended for people who have never received any vaccine but are at high risk of getting COVID-19, including old age/sick, immunocompromised people, and healthcare workers. This concept poses the question, “Should people who are already affected by COVID-19 need a vaccine?”. Studies comparing natural infection and hybrid immunity show that the latter immunity is superior to the former and unvaccinated individuals in terms of humoral and cell-mediated immunity. Therefore, integration of the history of COVID- 19 before vaccination and the collection of more seroprevalence information on the conditions can help to devise effective immunization strategies. 3. 2. At least one dose of COVID-19 vaccine is recommended for pregnant women. As discussed in this review, studies show that pregnant women are at higher risk of hospitalization due to COVID-19. Furthermore, since pregnant women, particularly ones with low education and low income, show vaccine hesitancy, they were encouraged to take the vaccine. However, vaccinated pregnant women have the same level of maternal and/or neonatal adverse events as compared to unvaccinated pregnant women. Thus, the benefit of vaccination in this population remains unclear and warrants more detailed clinical studies. Compared to healthy individuals, those with a higher risk were recommended for revaccination after 6 to 12 months of the most recent dose. Previous studies that assessed the safety, immunogenicity, and reactogenicity with booster doses after the primary vaccination with one, two, three, or more doses showed better protection and fewer systemic side effects than those that received only the primary dose. Additionally, studies showed that homologous boosters had fewer systemic side effects than heterologous boosters. However, the impact of SARS-CoV-2 infection-induced immunity after the first or booster vaccination on potential side effects later remains unknown. The WHO considers healthy infants/children aged 6 months to 17 years as low priority group for COVID-19 vaccination. In addition, vaccine hesitancy is observed among the parents of infants compared to school-going children. Nonetheless, studies showed no adverse events except for pain at the injection site, malaise, and fever for vaccinated children. However, the long-term effect of vaccination in this group, with or without COVID-19, remains unknown.

    Liver injury after COVID-19 vaccination: Current status and future perspectives · 2026 · DOI

  • The number of serum samples analyzed was limited, which may restrict the generalizability of the neutralization findings. As with many cohort-based studies, the infection histories of the participants and the vaccine formulations represented may not fully capture the current epidemiological landscape. In addition, undiagnosed or asymptomatic infections prior to Omicron cannot be excluded and may have influenced the observed neutralization responses. Furthermore, older variants of concern were included primarily for proof-of-principle comparisons and do not reflect strains that are currently dominant..

    Validation of an MLV-based SARS-CoV-2 pseudovirus neutralization assay substantiates L455S-mediated antibody escape · 2026 · DOI

  • The Claim That COVID-19 Vaccination Protected Australians from All-Cause Mortality Is Not Plausible Clare M.

    The Claim That COVID-19 Vaccination Protected Australians from All-Cause Mortality Is Not Plausible · 2026 · DOI

  • The occurrence of asymptomatic infection highlights the importance of periodic mass testing in addition to case-finding of symptomatic individuals; however, the field performance of LFIA tests should be validated.

    SARS CoV-2 seroprevalence and diagnostic accuracy during a COVID-19 outbreak in a major penitentiary complex in Brazil, June to July 2020 · 2022 · DOI

  • Titanium dioxide (TiO <ns3:sub>2</ns3:sub> ) coating of surfaces is a promising infection control measure, though to date has not been tested against SARS-CoV-2.

    Rapid inactivation of SARS-CoV-2 by titanium dioxide surface coating · 2021 · DOI

  • So far, studies evaluating semen quality and the occurrence of SARS-CoV-2 in semen of infected or proven recovered men are scarce and included a limited number of participants.

    Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19 · 2021 · DOI

  • Since the pathophysiology of COVID-19 remains not fully elucidated, studies are necessary to understand the real role of salivary glands and saliva in the taste alterations observed in COVID-19 patients.

    Altered taste in patients with COVID‐19: The potential role of salivary glands · 2020 · DOI

  • The reported taste disturbances in COVID-19-positive subjects have only been subjective in nature, and it remains unknown if patients have actual disturbances in their sense of taste or whether they are experiencing a disturbance in flavor, which is a combination of olfactory, gustatory, and trigeminal inputs (Bromley, 2000; Fitzgerald, 2020; Parma et al.

    Altered taste in patients with COVID‐19: The potential role of salivary glands · 2020 · DOI

  • Pleural involvement is not common; around 5-10% of patients can develop pleural effusion and little is known about the involvement of pleural structures in this new infection.

    SARS-CoV-2 in pleural fluid in a kidney transplant patient · 2020 · DOI

  • To date, little is known about the persistence of antibodies against SARS-CoV-2 in animals under natural conditions, in particular susceptible pets such as cat.

    Rehabilitation Services for Older People with Visual Impairments. · 2002 · DOI

  • Although GC content is recognized to have biological significance, its functional role in viruses remains poorly understood.

    GC content mismatch of transgene destabilizes RNA virus genomes · 2026 · DOI

  • In spite of three-year pandemic time caused by Covid-19, the trend and impact of the evolution of SARS-CoV-2 remain unclear.

    The potential impact of the spreading of highly transmissible Omicron variant XBB.1.5 and JN.1 on the evolution of SARS-CoV-2 · 2026 · DOI

Most-cited papers in SARS-CoV-2 and COVID-19 Research

Most recent work

Find a gap in your own SARS-CoV-2 and COVID-19 Research sub-topic

This page shows what the SARS-CoV-2 and COVID-19 Research literature already flags as unresolved. To narrow it to your specific question, run the guided finder — it searches the gap library on demand and checks candidates against 250M+ OpenAlex works.

Open the Research Gap Finder →

Related topics in Medicine

Substance Abuse Treatment and Outcomes
989 open questions
Artificial Intelligence in Healthcare and Education
607 open questions
Attention Deficit Hyperactivity Disorder
448 open questions
Physical Activity and Health
436 open questions
Smoking Behavior and Cessation
402 open questions
Innovations in Medical Education
364 open questions
Dementia and Cognitive Impairment Research
363 open questions
HIV/AIDS Research and Interventions
342 open questions
72 open questions have been extracted from the limitations and future-work passages of 729 SARS-CoV-2 and COVID-19 Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

Tools for your next paper

Gaps & Literature SearchFind open questions in any field — 120,000+ open gaps mined from our own library.Pre-CheckIs your paper ready? A Tier 1–5 acceptance probability in seconds.Journal FinderA ranked shortlist of target journals from a 17,500-venue index.Duplicate Publication CheckerCheck prior-publication & salami-slicing risk across 8 sources.Citation GeneratorFreeA DOI or title → APA, MLA, Vancouver, Chicago, BibTeX, RIS. No signup.Graphical Abstract MakerFreeTurn your findings into a colorblind-safe graphical abstract.

Compare the category — Honest roundups of the AI research tools, ours listed alongside the alternatives.

Command palette

Jump anywhere, run any action.