PCORI Biweekly COVID-19 Scan: Bivalent Booster Vaccines, Treatment for Post-COVID Conditions (August 18-31, 2022)
Briefing
The Briefing provides an at-a-glance view of some important developments in the information universe surrounding COVID-19. The views presented here are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders.
Updated booster shots targeting the BA.4 and BA.5 subvariants of the Omicron variant as well as the parent strain of SARS-CoV-2 were authorized by the FDA on August 31, 2022 (see Topics to Watch). This marks the first time that a COVID-19 vaccine was evaluated on mouse data instead of human trial results. However, this is standard practice for annual updates to the flu vaccine. Expediting variant-specific vaccines could offer more nimble protection while fulfilling the early promises of mRNA vaccines’ quick adaptability. Although the models share similarities, some uncertainty remains over how precise the extrapolation of mouse data is for COVID-19 compared with its use for quadrivalent influenza vaccination and whether the added benefit of a bivalent vaccine will be a game-changer or simply offers incremental improvement.
Not getting COVID-19 remains the only sure way to prevent post-COVID conditions (PCC). A recent estimate finds that such conditions are keeping about 4 million people from working, and there are many accounts of how people are suffering. New treatment options (see Topics to Watch) are slowly emerging but require better understanding of the mechanisms that are causing PCC symptoms. Micro-clots have been posited as a possible mechanism, among others. A new funding program from the Patient-Led Research Collaborative will prioritize research that looks specifically at knowledge gaps identified by patients.
ECRI Horizon Scanning has selected the topics below as those with potential for impact relative to COVID-19 in the United States within the next 12 months. All views presented are preliminary and based on readily available information at the time of writing.
Because these topics are rapidly developing, we cannot guarantee the accuracy of this information after the date listed on this publication. In addition, all views expressed in the commentary section are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders. Topics are listed in alphabetical order.
Omicron BA.4/BA.5-Adapted Bivalent Booster Vaccines to Prevent COVID-19
At a Glance
- Decreased COVID-19 vaccine efficacy against symptomatic disease from the highly prevalent Omicron variant of SARS-CoV-2 has led the FDA to urge vaccine manufacturers to add an Omicron BA.4/BA.5 component to their COVID-19 vaccines to improve efficacy.
- Moderna’s mRNA-1273.222 vaccine and Pfizer and BioNTech’s Omicron BA.4/BA.5-adapted vaccine are two bivalent COVID-19 vaccines being developed to target the Omicron subvariants BA.4 and BA.5 in addition to the original SARS-CoV-2 strain.
- Pfizer and BioNTech submitted their BA.4/BA.5-adapted bivalent vaccine candidate to the FDA for emergency use authorization (EUA) on August 22, 2022, and Moderna submitted its vaccine a day later, both citing preclinical and manufacturing data of the BA.4/BA.5-specific vaccines, as well as data from clinical trials of their BA.1-adapted bivalent vaccine candidates.
- Both vaccines were authorized by the FDA on August 31, 2022. The US Centers for Disease Control and Prevention (CDC) recommended the use of the updated boosters for people aged 12 years and older to target the BA.4/BA.5 Omicron subvariants.
- Moderna and Pfizer have entered into supply agreements with the US government to supply 66 million and 105 million doses, for about $26 and $30 per dose, respectively.
Description
The emergence of SARS-CoV-2 variants, including the highly prevalent Omicron variant, has led to a decrease in efficacy of COVID-19 vaccines against symptomatic disease. To combat this, the FDA recently advised manufacturers to add a SARS-CoV-2 Omicron BA.4/BA.5 component to their COVID-19 vaccines, with the aim of making booster doses available in the fall of 2022.
Pfizer (in collaboration with BioNTech) and Moderna are developing two Omicron BA.4/BA.5-adapted bivalent booster vaccines, Pfizer-BioNTech Omicron BA.4/BA.5-adapted vaccine and Moderna’s mRNA-1273.222. Both vaccines contain mRNA (genetic instructions) encoding for the SARS-CoV-2 spike proteins of the original SARS-CoV-2 strain, and the Omicron BA.4 and BA.5 subvariants, thus offering broad protection. CDC genomic surveillance data suggest that, as of August 27, 2022, about 92% of COVID-19 cases in the United States were attributed to the BA.4 and BA.5 Omicron subvariants, making them potentially important targets for the new COVID-19 vaccines.
The Pfizer-BioNTech Omicron BA.4/BA.5-adapted vaccine, for use in individuals aged 12 years or older, was submitted for EUA to the FDA on August 22, 2022, and Moderna’s mRNA-1273.222, for use in adults, was submitted on August 23, 2022. Moderna’s submission was based on preclinical and manufacturing data from the vaccines as well as from Moderna’s bivalent Omicron BA.1 candidate. Pfizer-BioNTech’s submission included preclinical and manufacturing data as well as clinical data from Pfizer-BioNTech’s bivalent Omicron BA.1 candidate. Further, a phase 2/3 trial of mRNA-1273.222 is ongoing, and a clinical trial of Pfizer-BioNTech’s Omicron BA.4/BA.5-adapated bivalent vaccine in individuals 12 years or older was expected to start in August 2022.
Both vaccines were authorized by FDA on August 31, 2022. Additionally, the CDC recommended the use of the updated COVID-19 booster shots for people aged 12 years and older to target the BA.4/BA.5 Omicron subvariants on September 1, 2022. The US government has entered into supply contracts with both manufacturers, securing an initial 66 million doses of mRNA-1273.222 for $1.74 billion or about $26 per dose, and 105 million doses (30 µg, 10 µg, and 3 µg) of the Pfizer original and Omicron-adapted COVID-19 vaccines for $3.2 billion or about $30 per dose.
Commentary
Decreased COVID-19 vaccine efficacy against symptomatic disease from the Omicron variant suggests the need for a bivalent booster vaccine to prevent and mitigate COVID-19.
Early feedback from ECRI internal stakeholders suggested that, if effective, BA.4/BA.5-adapted bivalent COVID-19 vaccines might improve patient and population health outcomes because they would target Omicron subvariants causing the majority of recent COVID-19 cases. New vaccines with the potential to mitigate SARS-CoV-2 infection and COVID-19 severity might decrease the overall burden on the health care system in both the short term (e.g., by reducing hospitalizations) and the long term (e.g., by reducing the need to treat post-COVID conditions).
Stakeholders also thought vaccine distribution might be impacted by a recent patent infringement lawsuit filed by Moderna claiming that Pfizer and BioNTech unlawfully copied its mRNA technology for the COVID vaccine. Misinformation about the need for a COVID-19 vaccine booster, “vaccine hesitancy” or “booster fatigue,” as well as controversy around the lawsuit, might negatively impact access and people’s interest in getting boosted. Health care disparities might increase for those with already limited access to vaccination.
- Category: Vaccines and prophylaxis
- Areas of potential impact: Patient health outcomes, population health outcomes, health disparities
Rintatolimod (Ampligen) to Treat Post-COVID Conditions
At a Glance
- Rintatolimod is an investigational RNA-based immunomodulatory treatment for post-COVID conditions (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—two poorly understood, often debilitating conditions that share severe fatigue as a hallmark symptom.
- Nearly one-third of patients diagnosed with COVID-19 develop PCC, according to estimates. The lack of FDA-approved treatments for PCC represents a major unmet medical need for effective treatments.
- A recent pilot study, performed within an expanded access program (EAP), suggested that rintatolimod was associated with a decrease in fatigue-related measures in 4 patients with PCC.
- Based partly on these data, the developer intends to submit an investigational new drug (IND) application to the FDA for a phase 2, randomized, controlled trial to investigate rintatolimod to treat PCC.
Description
Rintatolimod (Ampligen; AIM ImmunoTech, Inc, Ocala, Florida) is a treatment being investigated to treat PCC.
Rintatolimod has been studied to treat (although is not FDA-approved for) ME/CFS, a serious, long-term illness that affects many body systems and often prevents patients from doing their usual activities. People with ME/CFS experience severe fatigue and a variety of other symptoms, including issues with sleep, thinking and concentrating, pain, and dizziness. These characteristics overlap substantially with PCC, the long-term, potentially debilitating condition experienced by about one-third of patients diagnosed with COVID-19. Fatigue is the most common symptom of PCC, affecting about one-third of those diagnosed. Although the underlying mechanisms causing these conditions are incompletely understood, it has been proposed that persistent, low-grade infection, chronic inflammation, and/or immune system dysregulation might contribute to both ME/CFS and PCC.
Rintatolimod is an RNA-based drug and a selective Toll-like receptor 3 (TLR-3) activator thought to produce antiviral and immunomodulatory effects. In controlled phase 3 clinical trials in patients with severe ME/CFS, rintatolimod use was associated with an increase in exercise tolerance and decreased need for medication to treat symptoms. The drug’s developer announced in July 2022 that 4 patients enrolled in a 12-week pilot study of rintatolimod to treat post-COVID conditions, as part of an EAP, experienced a reduction in fatigue-related measures. As a result, the developer intends to initiate a phase 2 randomized controlled trial.
Although the potential cost of rintatolimod to treat PCC is unknown, the yearly cost of the drug to treat CFS has been estimated to be more than $40, 000. The drug is given intravenously at similar dosages across investigational indications.
Commentary
Because PCC remain poorly understood, novel, targeted therapies are challenging to design. Symptomatically related conditions, such as ME/CFS, might accelerate clinical development by yielding therapeutic candidates.
Early feedback from ECRI internal stakeholders suggested this “repurposing” of investigational treatments might allow patients to access effective treatments for PCC sooner. Stakeholders noted that much more clinical evidence is needed to support the potential benefits of this intervention, including determining the length of treatment. If rintatolimod is proven to be effective for PCC fatigue, its pairing with physical rehabilitation might further enhance its benefit.
Stakeholders thought rintatolimod’s relatively high cost and restricted availability to only a few clinical infusion therapy sites (through EAPs) might worsen socioeconomic disparities in health care access. If approved, health insurance coverage might lessen its cost to patients and could expand its availability to a greater number of sites. However, in turn, its intravenous-only delivery method could increase demands on caregivers.
- Category: Treatment
- Areas of potential impact: Patient outcomes, health care disparities, health care costs
Horizon scanning is a systematic process that serves as an early warning system to inform decision makers about possible future opportunities and threats. Health care horizon scanning identifies technologies, innovations, and trends with potential to cause future shifts or disruptions—positive or negative—in areas such as access to care, care delivery processes, care setting, costs of care, current treatment models or paradigms, health disparities, health care infrastructure, public health, and patient health outcomes.
The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning to better inform its patient-centered outcomes research investments. Initially, PCORI defined the HCHSS project scope to focus on interventions with high potential for disruption in the United States in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future.
In early 2020, the COVID-19 pandemic created a fast-moving, widespread public health crisis. In May 2020, PCORI expanded its HCHSS to elucidate the landscape of potentially impactful applications for COVID-19. The HCHSS COVID-19 supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with potential for high impact to patient outcomes—for individuals and populations—in the United States in the next 12 months.
The HCHSS COVID-19 supplement produces 3 main outputs:
- Biweekly COVID-19 Scans (eg, this document) provide ECRI Horizon Scanning with a vehicle to inform PCORI and the public in a timely manner of important topics of interest identified during ongoing scanning and topic identification or through the ECRI stakeholder survey process.
- Status Reports (quarterly) briefly list and describe all COVID-19-related topics identified, monitored, and recently archived.
- High Impact Reports (every 4 months) highlight those topics that ECRI internal stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, and information technology professionals) have identified as having potential for high impact relative to COVID-19 in the United States.
In May 2021, the COVID-19 supplement was modified and merged with the HCHSS. The Biweekly COVID-19 Scans continue, while the Status Reports and High Impact Reports were folded into the PCORI Horizon Scanning Database and High Potential Disruption Reports.
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Commentary in this COVID-19 Scan reflects preliminary views of ECRI Horizon Scanning and internal ECRI stakeholders.
The information contained in this document has not been vetted by other stakeholders.
We welcome your comments on this Scan. Send them by email to [email protected].
Posted: September 8, 2022
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