Messenger RNA Vaccines Research Articles

MRNA anti‐cancer vaccine research gains momentum

Ongoing research into the use of messenger RNA (mRNA) vaccines for the treatment of cancer has been expediated by the coronavirus pandemic because similar technology was used in the development of mRNA COVID‐19 vaccines. So how close are we now to the widespread clinical use of mRNA anti‐cancer vaccines?

Nucleic acid delivery by ionizable nanocarriers for brain disease treatment

AbstractThe successful application of messenger RNA vaccines in the market has demonstrated the potential of gene therapy in treating various diseases, including infectious diseases, autoimmune disorders, brain diseases, and other cancers. However, gene therapy faces great challenges in treating brain diseases such as brain tumors, infections, and strokes because the limitations of the blood‐brain barrier make it difficult for nucleic acid drugs to be delivered safely and effectively into the brain. Therefore, there is a high demand for carriers delivering nucleic acid drugs to the brain. Ionizable nanocarriers (INs) have great advantages in gene therapy due to their pH‐responsive properties, which facilitate the safe and efficient delivery of targets, responsive release in the disease microenvironment, and the protection of nucleic acids from degradation. To better understand INs and their potential as therapeutic vectors for brain diseases, the present review describes their biological properties, recent progress in the field, and promising applications. In particular, the related prospects and challenges are discussed to promote the further development of INs.

Myocarditis or Pericarditis Events After BNT162b2 Vaccination in Individuals Aged 12 to 17 Years in Ontario, Canada

The risk of myocarditis or pericarditis after COVID-19 messenger RNA vaccines varies by age and sex, and there is some evidence to suggest increasing risk with shorter intervals between dose 1 and 2 (ie, interdose interval). To estimate the incidence of reported myocarditis or pericarditis after BNT162b2 vaccine among adolescents and to describe the clinical information associated with these events. This was a population-based cohort study using passive vaccine safety surveillance data linked to the provincial COVID-19 vaccine registry. Included in the study were all adolescents aged 12 to 17 years in Ontario, Canada, who received 1 or more doses of BNT162b2 vaccine between December 14, 2020, and November 21, 2021, and reported an episode of myocarditis or pericarditis. Data were analyzed from December 15, 2021, to April 22, 2022. Receipt of BNT162b2 (Comirnaty [Pfizer-BioNTech]) vaccine. Reported incidence of myocarditis or pericarditis meeting level 1 to 3 of the Brighton Collaboration case definition per 100 000 doses of BNT162b2 administered by age group (12-15 years vs 16-17 years), sex, dose number, and interdose interval. All clinical information associated with symptoms, health care usage, diagnostic test results, and treatment at the time of the acute event were summarized. There were approximately 1.65 million doses of BNT162b2 administered and 77 reports of myocarditis or pericarditis among those aged 12 to 17 years, which met the inclusion criteria during the study period. Of the 77 adolescents (mean [SD] age, 15.0 [1.7] years; 63 male individuals [81.8%]), 51 (66.2%) developed myocarditis or pericarditis after dose 2 of BNT162b2. Overall, 74 individuals (96.1%) with an event were assessed in the emergency department, and 34 (44.2%) were hospitalized (median [IQR] length of stay, 1 [1-2] day). The majority of adolescents (57 [74.0%]) were treated with nonsteroidal anti-inflammatory drugs only, and 11 (14.3%) required no treatment. The highest reported incidence was observed among male adolescents aged 16 to 17 years after dose 2 (15.7 per 100 000; 95% CI, 9.7-23.9). Among those aged 16 to 17 years, the reporting rate was highest in those with a short (ie, ≤30 days) interdose interval (21.3 per 100 000; 95% CI, 11.0-37.2). Results of this cohort study suggest that there was variation in the reported incidence of myocarditis or pericarditis after BNT162b2 vaccine among adolescent age groups. However, the risk of these events after vaccination remains very rare and should be considered in relation to the benefits of COVID-19 vaccination.

A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses via α-tocopherol component.

Adjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known. To characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component. This study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants.

Persistence of Antibodies Six Months after Three COVID-19 mRNA Vaccine Doses in Patients with Inflammatory Bowel Disease.

Lay Summary We evaluated antibody concentrations 6 months after a third coronavirus disease 2019 messenger RNA vaccine dose in patients with inflammatory bowel diseases. Almost all patients had an antibody response, and those with a previous SARS-CoV-2 infection had higher antibody concentrations.

Sleep Disturbance and SARS-CoV-2 Vaccinations in Patients With Chronic Inflammatory Disease.

Immunocompromised patients with chronic inflammatory disease (CID) may have experienced additional psychosocial burden during the COVID-19 pandemic due to their immunocompromised status. This study was undertaken to determine if vaccination would result in improved patient-reported outcomes longitudinally among individuals with CID undergoing SARS-CoV-2 vaccination regardless of baseline anxiety. Data are from a cohort of individuals with CID from 2 sites who underwent SARS-CoV-2 vaccination. Participants completed 3 study visits before and after 2 messenger RNA vaccine doses in the initial vaccination series when clinical data were collected. Patient-reported outcomes were measured using the Patient-Reported Outcomes Measurement Information System 29-item Health Profile and expressed as T scores, with 2 groups stratified by high and low baseline anxiety. Mixed-effects models were used to examine longitudinal changes, adjusting for age, sex, and study site. A total of 72% of the cohort was female with a mean ± SD age of 48.1 ± 15.5 years. Overall, sleep disturbance improved following both doses of SARS-CoV-2 vaccinations, and anxiety decreased after the second dose. Physical function scores worsened but did not meet the minimally important difference threshold. When stratifying by baseline anxiety, improvement in anxiety, fatigue, and social participation were greater in the high anxiety group. Physical function worsened slightly in both groups, and sleep disturbance improved significantly in the high anxiety group. Sleep disturbance decreased in a significant and meaningful way in patients with CID upon vaccination. In patients with higher baseline anxiety, social participation increased, and anxiety, fatigue, and sleep disturbance decreased. Overall, results suggest that SARS-CoV-2 vaccination may improve mental health and well-being, particularly among those with greater anxiety.

Sustained Myocarditis following Messenger RNA Vaccination against Coronavirus Disease 2019: Relation to Neutralizing Antibody and Amelioration by Low-Dose Booster Vaccination

We recently reported that sub-acute myocarditis occurred following the initial two doses of messenger RNA-based vaccination against coronavirus disease 2019 (0.3 mL Comirnaty®) in elderly Japanese patients with cardiac dysfunction. The present retrospective study of 76 patients revealed that myocarditis following the initial doses persisted for 12 months, was associated with low levels of neutralizing antibodies, and was ameliorated by reducing the third vaccine dose. Low neutralizing antibody levels (<220 U/mL) after the initial doses were an independent predictor of persistent clinical events, defined as death or marked changes in brain natriuretic peptide levels. When the third dose was reduced (0.1 mL), changes in brain natriuretic peptide levels were significantly smaller (p = 0.02, n = 25), no deaths occurred due to heart failure, and neutralizing antibody levels increased 41-fold (p < 0.001) compared with the initial doses. Reduced booster doses could facilitate the worldwide distribution of messenger RNA vaccines.

Safety Monitoring of COVID-19 Vaccines: Perspective from the European Medicines Agency.

Prior to deployment of coronavirus disease 2019 (COVID-19) vaccines in the European Union in 2021, a high vaccine uptake leading to an unprecedented volume of safety data from spontaneous reports and real-world evidence, was anticipated. The European Medicines Agency (EMA) implemented specific activities to ensure enhanced monitoring of emerging vaccine safety information, including intensive monitoring of reports of adverse events of special interest and the use of observed-to-expected analyses. The EMA also commissioned several independent observational studies using a large network of electronic healthcare databases and primary data collection via mobile and web-based applications. This preparedness was key for two high-profile safety signals: thrombosis with thrombocytopenia syndrome (TTS), a new clinical entity associated with adenovirus-vectored vaccines, and myocarditis/pericarditis with messenger RNA vaccines. With no existing case definition nor background rates, the signal of TTS posed particular challenges. Nevertheless, it was rapidly identified, evaluated, contextualized and the risk minimized thanks to close surveillance and an efficient use of available evidence, clinical expertise and flexible regulatory tools. The two signals illustrated the complementarity between spontaneous and real-world data, the former enabling rapid risk identification and communication, the latter enabling further characterization. The COVID-19 pandemic has tremendously enhanced the development of tools and methods to harness the unprecedented volume of safety data generated for the vaccines. Areas for further improvement include the need for better and harmonized data collection across Member States (e.g., stratified vaccine exposure) to support signal evaluation in all population groups, risk contextualization, and safety communication.

Comparison of COVID-19 Vaccine-Associated Myocarditis and Viral Myocarditis Pathology.

The COVID-19 pandemic has led to significant loss of life and severe disability, justifying the expedited testing and approval of messenger RNA (mRNA) vaccines. While found to be safe and effective, there have been increasing reports of myocarditis after COVID-19 mRNA vaccine administration. The acute events have been severe enough to require admission to the intensive care unit in some, but most patients fully recover with only rare deaths reported. The pathways involved in the development of vaccine-associated myocarditis are highly dependent on the specific vaccine. COVID-19 vaccine-associated myocarditis is believed to be primarily caused by uncontrolled cytokine-mediated inflammation with possible genetic components in the interleukin-6 signaling pathway. There is also a potential autoimmune component via molecular mimicry. Many of these pathways are similar to those seen in viral myocarditis, indicating a common pathophysiology. There is concern for residual cardiac fibrosis and increased risk for the development of cardiomyopathies later in life. This is of particular interest for patients with congenital heart defects who are already at increased risk for fibrotic cardiomyopathies. Though the risk for vaccine-associated myocarditis is important to consider, the risk of viral myocarditis and other injury is far greater with COVID-19 infection. Considering these relative risks, it is still recommended that the general public receive vaccination against COVID-19, and it is particularly important for congenital heart defect patients to receive vaccination for COVID-19.

The conundrum of COVID-19 mRNA vaccine-induced anaphylaxis.

Novel messenger RNA (mRNA) vaccines have proven to be effective tools against coronavirus disease 2019, and they have changed the course of the pandemic. However, early reports of mRNA vaccine-induced anaphylaxis resulted in public alarm, contributing toward vaccine hesitancy. Although initial reports were concerning for an unusually high rate of anaphylaxis to the mRNA vaccines, the true incidence is likely comparable with other vaccines. These reactions occurred predominantly in young to middle-aged females, and many had a history of allergies. Although initially thought to be triggered by polyethylene glycol (PEG), lack of reproducibility of these reactions with subsequent dosing and absent PEG sensitization point away from an IgE-mediated PEG allergy in most. PEG skin testing has poor posttest probability and should be reserved for evaluating non-vaccine-related PEG allergy without influencing decisions for subsequent mRNA vaccination. Immunization stress-related response can closely mimic vaccine-induced anaphylaxis and warrants consideration as a potential etiology. Current evidence suggests that many individuals who developed anaphylaxis to the first dose of an mRNA vaccine can likely receive a subsequent dose after careful evaluation. The need to understand these reactions mechanistically remains critical because the mRNA platform is rapidly finding its way into other vaccinations and therapeutics.

MRNA vaccines: The future of prevention of viral infections?

Messenger RNA (mRNA) vaccines against COVID-19 are the first authorized biological preparations developed using this platform. During the pandemic, their administration has been proven to be a life-saving intervention. Here, we review the main advantages of using mRNA vaccines, identify further technological challenges to be met during the development of the mRNA platform, and provide an update on the clinical progress on leading mRNA vaccine candidates against different viruses that include influenza viruses, human immunodeficiency virus 1, respiratory syncytial virus, Nipah virus, Zika virus, human cytomegalovirus, and Epstein-Barr virus. The prospects and challenges of manufacturing mRNA vaccines in low-income countries are also discussed. The ongoing interest and research in mRNA technology are likely to overcome some existing challenges for this technology (e.g., related to storage conditions and immunogenicity of some components of lipid nanoparticles) and enhance the portfolio of vaccines against diseases for which classical formulations are already authorized. It may also open novel pathways of protection against infections and their consequences for which no safe and efficient immunization methods are currently available.

Message from the Winner

I would like to express my sincere gratitude for the MURAKAMI Suminao Award for Disaster Research 2022 and the JDR Award for the Most Contributory Reviewer 2022. It has been a great pleasure to serve on the editorial board for many years, and I have had the opportunity to talk with distinguished members of the editorial board who specialize in natural disasters such as earthquakes, volcanoes, and floods, which are completely outside my field of expertise, biology and medicine, and who have greatly broadened my perspective. The saying goes that disasters come just when you forget about them, but we have been in a situation recently where disasters come before we forget about them. There have been so many disasters: the panic that began with the discovery of cattle infected with bovine spongiform encephalopathy in Japan in 2001, the simultaneous terrorist attacks in the U.S. and the U.S. military invasion of Afghanistan around the same time, the poisoning of frozen dumplings made in China in 2007, the Tohoku Earthquake and Fukushima Daiichi Nuclear Power Plant accident in 2011, the COVID-19 problem that has continued from 2019 to the present, the invasion of Ukraine by Russia in 2022 and the resulting energy crisis and food shortages, as well as earthquakes, torrential rains, landslides, and typhoons that have occurred every year. The purpose of JDR, I believe, would be to stimulate research on these disasters, thereby providing a basis for the development of technologies for disaster prevention and control. In this regard, I have been concerned about the distance between science and technology: in the case of COVID-19, research on the causative virus, combined with messenger RNA vaccine technology, led to the fastest vaccine ever developed. On the other hand, the development of a cure has been slow, and the only treatment for pneumonia has been the old-fashioned one. Recently, antiviral drugs have been developed, but their efficacy has yet to be determined. There are many reasons for the distance between science and technology, and I hope that the research results published in JDR will play a role in reducing that distance.

Transition of Antibody Titers after SARS-CoV-2 mRNA Vaccination in Japanese Healthcare Workers.

Since February 2021, healthcare workers in Japan have been preferentially vaccinated with a messenger RNA vaccine (BNT162b2; Pfizer/BioNTech) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While many studies have confirmed that this vaccine is highly effective in reducing hospitalization and deaths from coronavirus disease 2019 (COVID-19), antibody titers tend to decline at 3 months after vaccination, leading to a risk of breakthrough infections. Thus, information is needed to support the decision regarding the 3rd vaccination. In this study, we investigated the transition of anti-SARS-CoV-2 spike protein receptor-binding domain (RBD) IgG and neutralizing antibody titers in 37 vaccinated Japanese healthcare workers. Samples were collected 6 times starting before vaccination until 6 months after the second vaccination. The levels of anti-SARS-CoV-2 RBD IgG peaked 1 week after the 2nd vaccination, then declined over time and decreased to < 10% at 6 months after the 2nd vaccination. Additionally, approximately one-third of the healthcare workers were seronegative for the Omicron variant 6 months after the 2nd vaccination. Workers with low anti-SARS-CoV-2 RBD IgG levels also had low neutralizing antibody titers. These data support booster dose administration for healthcare workers, especially those with low anti-SARS-CoV-2 RBD IgG levels.

Is Vaccination Against COVID-19 Associated With Inflammatory Bowel Disease Flare? Self-Controlled Case Series Analysis Using the UK CPRD.

To investigate the association between vaccination against coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) flare. Patients with IBD vaccinated against COVID-19 who consulted for disease flare between December 1, 2020, and December 31, 2021, were ascertained from the Clinical Practice Research Datalink. IBD flares were identified using consultation and corticosteroid prescription records. Vaccinations were identified using product codes and vaccination dates. The study period was partitioned into vaccine-exposed (vaccination date and 21 days immediately after), prevaccination (7 days immediately before vaccination), and the remaining vaccine-unexposed periods. Participants contributed data with multiple vaccinations and IBD flares. Season-adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) were calculated using self-controlled case series analysis. Data for 1911 cases with IBD were included; 52% of them were female, and their mean age was 49 years. Approximately 63% of participants had ulcerative colitis (UC). COVID-19 vaccination was not associated with increased IBD flares in the vaccine-exposed period when all vaccinations were considered (aIRR [95% CI] 0.89 [0.77-1.02], 0.79 [0.66-0.95], and 1.00 [0.79-1.27] in IBD overall, UC, and Crohn's disease, respectively). Analyses stratified to include only first, second, or third COVID-19 vaccinations found no significant association between vaccination and IBD flares in the vaccine-exposed period (aIRR [95% CI] 0.87 [0.71-1.06], 0.93 [0.75-1.15], and 0.86 [0.63-1.17], respectively). Similarly, stratification by COVID-19 before vaccination and by vaccination with vectored DNA or messenger RNA vaccine did not reveal an increased risk of flare in any of these subgroups. Vaccination against COVID-19 was not associated with IBD flares regardless of prior COVID-19 infection and whether messenger RNA or DNA vaccines were used.

Consenso de expertos sobre el diagnóstico y el tratamiento de la miocarditis asociada con infección o vacunación contra el SARS-CoV-2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has revealed several cardiovascular complications, including myocarditis caused by SARS-CoV-2 infection (COVID-19) or after messenger RNA vaccine administration. Because of the high prevalence of COVID-19, the expansion of vaccination programs, and the appearance of new information on myocarditis in these contexts, there is a need to condense the knowledge acquired since the start of the pandemic. To meet this need, this document was drafted by the Myocarditis Working Group of the Heart Failure Association of the Spanish Society of Cardiology, with the collaboration of the Spanish Agency for Medicines and Health Products (AEMPS). The document aims to address the diagnosis and treatment of cases of myocarditis associated with SARS-CoV-2 infection or messenger RNA vaccine administration.

The dose- and time-dependent effectiveness and safety associated with COVID-19 vaccination during pregnancy: a systematic review and meta-analysis

ObjectivesThis study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines. MethodsThe Cochrane Library, Embase, PubMed, Web of Science, ClinicalKey, and other COVID-19 datasets were searched from December 2019 to May 2022. Case-control studies and prospective cohort studies of COVID-19 vaccine effectiveness and safety in pregnant women were included. ResultsFrom day 11 to day 13, after the first dose of the COVID-19 messenger RNA vaccine, the effectiveness was 54% (95% confidence interval: 0.33-0.69). On days 14 to 27, the effectiveness was 59%. There was a 14% increase in vaccine effectiveness 28 days after the first dose was given. The inactivated vaccines showed similar effectiveness. The proportions of placental abruptions, postpartum hemorrhages, miscarriages, stillbirths, premature births, and small for gestational age infants were not significantly different between vaccinated and nonvaccinated pregnant women. Fatigue and fever were also not associated with pregnancy. ConclusionOur findings affirm that the effectiveness varies for different types of vaccines and is significantly and positively correlated with time in the pregnant population. COVID-19 vaccines have also been deemed safe for pregnant women. Thus, we developed a comprehensive understanding of the role of vaccines in pregnant women.

Immunogenicity of a fractional or full third dose of AZD1222 vaccine or BNT162b2 messenger RNA vaccine after two doses of CoronaVac vaccines against the Delta and Omicron variants

ObjectivesThe study aimed to compare the immunogenicity and safety of fractional (half) third doses of heterologous COVID-19 vaccines (AZD1222 or BNT162b2) to full doses after the two-dose CoronaVac and when boosting after three different extended intervals. MethodsAt 60-<90, 90-<120, or 120-180 days intervals after the two-dose CoronaVac, participants were randomized to full-dose or half-dose AZD1222 or BNT162b2, followed up at day 28, 60, and 90. Vaccination-induced immune responses to Ancestral, Delta, and Omicron BA.1 strains were evaluated by antispike, pseudovirus, and microneutralization and T cell assays. Descriptive statistics and noninferiority cut-offs were reported as geometric mean concentration or titer and concentration or titer ratios comparing baseline to day 28 and day 90 and different intervals. ResultsNo safety concerns were detected. All assays and intervals showed noninferior immunogenicity between full doses and half doses. However, full-dose vaccines and/or longer 120-180-day intervals substantially improved the immunogenicity (measured by antispike or measured by pseudotyped virus neutralizing titers 50; P <0.001). Seroconversion rates were over 90% against the SARS-CoV-2 strains by all assays. Immunogenicity waned more quickly with half doses than full doses but remained high against the Ancestral or Delta strains. Against Omicron, the day 28 immunogenicity increased with longer intervals than shorter intervals for full-dose vaccines. ConclusionImmune responses after day 28 when boosting at longer intervals after the two-dose CoronaVac was optimal. Half doses met the noninferiority criteria compared with the full dose by all the immune assays assessed.

A 6-Week Time Period May not be Sufficient to Identify Potential Adverse Events Following COVID-19 Vaccination

Background. Messenger RNA (mRNA) vaccines have been widely used as the main sanitary measure destined to fight the COVID-19 pandemic. Rapidly purported as being “safe and effective”, this new generation of vaccines is radically different from those developed traditionally and for which potentially associated adverse events (AEs) are considered through a standard 6-week post-vaccination period. Hypothesis. Here, we posit that the reporting period for AEs related to the COVID-19 vaccines may need to be longer. Method. In this retrospective, observational study, we aimed to assess the chronology of new/worsening ailments occurring after the administration of COVID-19 vaccines based on the changes to the participants’ pharmacological records. Patients vaccinated against COVID-19 and experiencing health-related events during the study period (between September 30, 2021 and July 15, 2022) were included and the changes to their pharmacological records were analyzed. Results. One hundred and twelve (112) adult patients (63 men, 49 women; 67.54 ± 14.55 years-old; mean ± standard deviation) have reported changes to their pharmacological record following health-related events, which occurred 11.57 weeks (median; range 0.04-47.14) following their last COVID-19 injection of 3 doses (median; range 1-4). The most frequent medical ailments that appeared or worsened were cardiovascular diseases (CVD; N=61), cancer (N=31), respiratory diseases (RD; N=22) and zona (N=10), half of which occurred after the second dose. Nineteen (19) patients (10 men, 9 women; 78.2 ± 11.4 years-old) died on average 17.14 weeks (SD 13.71) after their last injection. Conclusion. Most (76.1%) of the health-related events experienced by patients vaccinated against COVID-19 occurred beyond the 6-week period prescribed by the health authorities. Our findings call for further investigations and an extension of the post-vaccination AE reporting period.

Comprehensive identification of potential immune-related genes related to tumor biological behavior and their significance in the treatment of head and neck squamous cell carcinoma with a messenger RNA (mRNA) vaccine

Comprehensive identification of potential immune-related genes related to tumor biological behavior and their significance in the treatment of head and neck squamous cell carcinoma with a messenger RNA (mRNA) vaccine

Antiviral medications for mild-to-moderate COVID-19 in Japan: a gap of timing between clinical trials and real-world scenarios in a fast-changing pandemic.

The rapid spread of a novel type of coronavirus infection, coronavirus disease 2019 (COVID-19) has made it difficult to implement the results of clinical trials in real-world situations. After the emergence of the Omicron variant and messenger RNA vaccine, a combination of less virulent but more contagious viruses and more people with protective immunity has resulted in a larger number of patients with less severe, mild-to-moderate COVID-19. Many patients with severe conditions did not have extensive viral pneumonia frequently seen in the "pre-Omicron" era but had serious complications due to aggravation of underlying comorbidities or secondary bacterial infections. Most clinical trials for new antiviral drugs were conducted in the "pre-Omicron" period based on a different set of background patient characteristics than the ones seen in the Omicron period. Understanding situational differences due to the gap in the timing between clinical trials and the practical use of drugs for COVID-19 will assist in developing an effective treatment strategy in real-world practice. In this seminar, we reviewed antiviral treatments for mild-to-moderate COVID-19 from the viewpoint of the difference in patient backgrounds between clinical trials and real-world studies, focusing on drugs currently used in Japan.