Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an ongoing global health challenge. As of August 16, 2023, SARS-CoV-2 has led to over 770 million cases of coronavirus disease 2019 (COVID-19), including 7 million deaths worldwide, and has caused societal, economic, and healthcare system disruptions.
COVID-19 vaccination has been a cornerstone of the pandemic response, as vaccines may provide protection against COVID-19. COVID-19 vaccinations have been estimated to have prevented tens of millions of deaths worldwide in the first year alone after COVID-19 vaccines became available in December 2020.
It is a nucleoside-modified messenger RNA (mRNA) vaccine encoding the full-length spike (S) protein of the Original (Wuhan Hu-1) SARS-COV-2 strain. This vaccine, referred to as the Pfizer-BioNTech COVID-19 Vaccine (Original monovalent), has been instrumental in reducing the spread of the virus and preventing severe illness. However, the virus continues to evolve, and new variants, such as the Omicron lineage, have emerged.
To address the changing landscape of the pandemic, the Pfizer-BioNTech COVID-19 Vaccine was updated to include the S-glycoprotein of Original and S-glycoprotein of SARS-CoV-2 Omicron variant lineages BA.4 and BA.5, collectively referred to as the Pfizer-BioNTech COVID-19 Vaccine, Bivalent. This update aimed to enhance the vaccine’s effectiveness against the evolving virus.
On April 18, 2023, the U.S. Food and Drug Administration (FDA) authorized the use of the Pfizer-BioNTech and Moderna bivalent (Original and Omicron BA.4/BA.5) COVID-19 vaccines for all individuals 6 months of age and older.
This authorization allowed for a single dose in most adults and pediatric populations, two or three doses in the youngest pediatric populations, an additional dose for persons 65 years of age and older, and additional age-appropriate doses for persons with certain kinds of immunocompromise.
As a result, FDA no longer authorized the use of monovalent Moderna and Pfizer-BioNTech COVID-19 vaccines containing the mRNA encoding the spike protein of the original SARS-CoV-2 virus. These decisions were made based on a thorough review of the available data.
While the bivalent COVID-19 vaccines have shown effectiveness against various sublineages of the Omicron variant, studies have indicated a gradual decrease in effectiveness over time, and lower neutralizing antibody titers against certain Omicron sublineages compared to the matched BA.4/BA.5 sublineage. This raised the need for an updated strain composition to align more closely with the currently circulating Omicron sublineages.
The Vaccines and Related Biological Products Advisory Committee (VRBPAC) convened to discuss and make recommendations on the selection of strain(s) for updated COVID-19 vaccines. On June 15, 2023, VRBPAC voted to recommend an update of the current COVID-19 vaccine composition to a monovalent XBB-lineage, with preference for the XBB.1.5 sublineage. FDA subsequently advised manufacturers to develop vaccines with a monovalent XBB.1.5 composition for the 2023-2024 Formula.
Pfizer/BioNTech, on June 23, 2023, requested authorization of their COVID-19 vaccine to include the 2023-2024 Formula as a 3-dose series at 3 µg for individuals 6 months to less than 5 years of age, and as a single dose at 10 µg for individuals 5 to less than 12 years of age. They also requested authorization for the use of additional doses in individuals with certain kinds of immunocompromise in the age range of 6 months through 11 years.
Importantly, the safety profile of the updated Pfizer BioNTech COVID-19 Vaccine (2023-2024 Formula) is similar to its predecessors, the Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) and Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5).
SARS-CoV-2, the Virus Behind COVID-19
SARS-CoV-2, a Zoonotic Menace
The world first became aware of SARS-CoV-2 in late 2019 when it was identified in patients suffering from pneumonia of an unknown origin. This novel virus, now infamous as the causative agent of the coronavirus disease 2019 (COVID-19), quickly spread globally, challenging healthcare systems and societies. SARS-CoV-2 is a member of the coronavirus family, with bats considered the probable natural reservoir.
COVID-19: A Complex and Variable Disease
As of August 16, 2023, SARS-CoV-2 had infected over 770 million people worldwide, resulting in an estimated 7 million deaths. However, COVID-19 is not a uniform disease; its symptoms and severity can vary greatly. Some individuals experience no symptoms or mild illness, while others, particularly those over 65 and those with underlying health conditions, develop severe respiratory problems, such as pneumonia and acute respiratory distress syndrome, leading to multiorgan failure and death.
Long-lasting Effects and Impact on Children
Most adults with COVID-19 recover within 1 to 2 weeks, but some continue to experience symptoms for months. Children generally exhibit milder symptoms, with fever and cough being the most common. However, the emergence of the Omicron variant in January 2022 has led to an unexpected rise in hospitalizations among infants under 6 months old, mirroring rates seen in adults aged 65 to 74.
The Toll in the United States
In the United States, the Centers for Disease Control and Prevention (CDC) reported over 6.3 million COVID-19-related hospitalizations and 1.1 million deaths. The elderly (those 65 and older) accounted for a significant proportion of both cases and deaths, while individuals under 18 represented a smaller share.
Factors Driving Surges in Cases
Throughout the pandemic, surges in SARS-CoV-2 activity, resulting in increased cases, hospitalizations, and deaths, have been influenced by various factors. These include the emergence of variants with greater transmissibility and virulence, the relaxation of public health measures, and seasonal variations typical of respiratory viruses.
The Role of Vaccines
COVID-19 vaccines based on the original Wuhan-HU-1 strain were introduced in the U.S. in December 2020. These vaccines were initially effective but faced challenges from rapidly spreading variants, including the Omicron variant. Bivalent vaccines targeting both the original strain and Omicron variants were deployed in September 2022.
The Omicron Challenge
The Omicron variant has been particularly formidable, continuously evolving into distinct sublineages with spike gene mutations and increased resistance to post-vaccination and post-infection immunity. The XBB sublineage, in particular, has dominated, with variants like XBB.1.5 and XBB.1.16 spreading rapidly due to changes in the spike protein and other genomic regions.
Continued Evolution and Uncertainty
SARS-CoV-2’s evolution remains unpredictable, with intrinsic viral factors, host immune responses, and non-viral factors shaping the emergence of new variants. Ongoing global surveillance and assessments of preventive and therapeutic interventions are crucial as the virus continues to adapt.
Authorized and Approved Vaccines and Therapies for COVID-19
Vaccines and Therapies: A Vital Arsenal
To combat the COVID-19 pandemic, a range of vaccines and therapies have been developed and authorized for use in the United States. These tools are crucial in the battle against SARS-CoV-2.
Comirnaty and Pfizer-BioNTech COVID-19 Vaccine
Comirnaty (2023-2024 Formula), manufactured by Pfizer for BioNTech, is an FDA-approved vaccine for individuals aged 12 and older. It contains mRNA encoding the spike glycoprotein of SARS-CoV-2 Omicron variant lineage XBB.1.5. Additionally, Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5), is authorized for various age groups under EUA, offering protection against multiple SARS-CoV-2 variants.
Spikevax and Moderna COVID-19 Vaccine
Spikevax (2023-2024 Formula), manufactured by Moderna, is an FDA-approved vaccine for individuals aged 12 and older, containing mRNA encoding the spike protein of SARS-CoV-2 Omicron variant lineage XBB.1.5. The Moderna COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5), is also authorized under EUA, providing a similar range of protection for different age groups.
Novavax COVID-19 Vaccine, Adjuvanted
The Novavax COVID-19 Vaccine, Adjuvanted, offers a different approach, using recombinant S protein from the original SARS-CoV-2 strain. It is authorized for use in individuals aged 12 and older, with particular recommendations for booster doses.
Therapies for COVID-19
In addition to vaccines, several therapies have been approved or authorized for the treatment of COVID-19, depending on the patient’s condition and risk factors.
- Veklury (remdesivir) is approved for treating adults and pediatric patients with COVID-19, especially those at high risk of severe disease.
- Paxlovid (nirmatrelvir and ritonavir) is approved for the treatment of mild-to-moderate COVID-19 in adults at high risk for progression to severe disease.
- Olumiant (baricitinib) and Actemra (Tocilizumab) are approved for hospitalized adults with specific respiratory requirements.
Emergency use authorized therapies
Several therapies have received emergency use authorization for pre-exposure prophylaxis, post-exposure prophylaxis, and treatment of COVID-19, depending on patient characteristics and risk factors. These include oral antivirals like Paxlovid and Lagevrio, SARS-CoV-2-targeting monoclonal antibodies, and immune modulators like Kineret and Gohibic.
COVID-19 Convalescent Plasma
High-titer COVID-19 convalescent plasma is authorized for treating patients with immunosuppressive diseases or receiving immunosuppressive treatment, either in outpatient or inpatient settings.
As the COVID-19 pandemic continues to evolve, the availability and effectiveness of these vaccines and therapies remain essential tools in the fight against SARS-CoV-2 and its variants. Ongoing research, monitoring, and adaptation of strategies will be crucial to managing this ever-changing global health challenge.
Rationale for Strain Change in COVID-19 Vaccines
Current Effectiveness of Authorized Bivalent COVID-19 Vaccines and Need for a Strain Update
In the wake of the emergence of the Omicron variant and its various sublineages, the landscape of COVID-19 vaccination underwent significant changes. The Omicron variant, with its sublineages such as BA.1, BA.4/BA.5, and others, prompted an evolution in vaccine strategies. In response to emerging data on the effectiveness of bivalent COVID-19 vaccines compared to monovalent ones, the FDA took decisive action.
On August 31, 2022, the FDA authorized the use of Moderna COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) and Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) for booster doses in individuals aged 18 or 12 years and older, respectively. Concurrently, they revised the scope of authorization for the manufacturers’ monovalent vaccines, removing their use as a booster dose in these age groups.
Subsequent to these authorizations, further observational data indicated that bivalent COVID-19 vaccines offered enhanced protection against Omicron sublineages, particularly BA.4/BA.5, compared to the original monovalent vaccines. This improved protection against circulating variants laid the groundwork for transitioning to bivalent COVID-19 vaccines for all doses authorized in individuals aged 6 months and older, as well as supporting periodic updates to the strain composition of these vaccines. Additionally, it was deemed reasonable to expect that a single dose of bivalent COVID-19 vaccines could effectively prevent serious or life-threatening conditions caused by SARS-CoV-2, including various Omicron sublineages.
In April 2023, the FDA authorized the use of Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) and Moderna COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) for all doses in individuals aged 6 months and older. Single-dose regimens were authorized for individuals aged 5 or 6 years and older, respectively. Moreover, additional doses were authorized for individuals aged 65 and older and for those with certain forms of immunocompromise.
Despite these developments, SARS-CoV-2 continued to evolve into distinct sublineages characterized by additional mutations. Real-world effectiveness studies suggested that the current bivalent vaccines maintained their protective efficacy against the currently circulating sublineages of Omicron, including XBB.1.5. However, there was an observed inverse relationship between the time since vaccination and vaccine effectiveness, with the effectiveness against Omicron sublineages waning over time. Studies also indicated lower neutralizing antibody titers induced by the current bivalent COVID-19 vaccines against XBB-related sublineages compared to the matched BA.4/BA.5 sublineage. This accumulating data supported the necessity of an updated strain composition for COVID-19 vaccines to more closely match the circulating Omicron sublineages.
Recommendation for the 2023-2024 Formula of COVID-19 Vaccines in the U.S.
To address the evolving landscape of SARS-CoV-2 and the need for updated vaccines, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) took on the responsibility of recommending strains to be included in the 2023-2024 Formula of COVID-19 vaccines. In their January 26, 2023 meeting, the FDA stated its intention to assess SARS-CoV-2 evolution at least annually, commencing the review in the spring of each year, and convene the VRBPAC in June to determine the strain selection for the upcoming fall vaccination season.
Analysis of SARS-CoV-2 evolution data indicated that XBB sublineages dominated the virus variants circulating in the U.S. in early June 2023. Although XBB.1.5 had declined, XBB.1.16 was on the rise, and XBB.2.3 was slowly increasing in proportion. This suggested that XBB.1.16 might become the dominant sublineage by fall 2023, with others continuing to evolve.
Despite these changes, the amino acid sequences of XBB.1.5, XBB.1.16, and XBB.2.3 spike proteins showed similarities, with few amino acid differences. Evidence suggested little to no further immune evasion from these new amino acid substitutions in the XBB.1.16 spike protein compared to XBB.1.5. However, the available evidence indicated that the currently available bivalent COVID-19 vaccines were less effective against currently circulating variants, particularly XBB-lineage viruses, than against previous strains of SARS-CoV-2.
Considering this evidence, the VRBPAC convened on June 15, 2023, to discuss the strain composition for the 2023-2024 Formula of COVID-19 vaccines in the U.S. Sublineages such as XBB.1.5, XBB.1.16, and XBB.2.3 were under consideration. The Committee’s decision was unanimous, with 21 members voting in favor and none opposing, to recommend updating the current vaccine composition to a monovalent XBB-lineage for the 2023-2024 Formula. Based on the totality of the evidence, the FDA advised manufacturers to develop vaccines with a monovalent XBB.1.5 composition for the 2023-2024 Formula of COVID-19 vaccines in the U.S.
Regulatory Considerations for EUA of a Bivalent COVID-19 Vaccine with an Omicron Component
In the relentless battle against the COVID-19 pandemic, regulatory agencies have played a pivotal role in ensuring the safety and efficacy of vaccines. The emergence of new variants, such as the Omicron variant, has necessitated adaptations in vaccine formulations. This chapter delves into the regulatory considerations for obtaining Emergency Use Authorization (EUA) for a bivalent COVID-19 vaccine, particularly focusing on an Omicron component.
U.S. Requirements to Support Issuance of an EUA for a Biological Product
The U.S. Department of Health and Human Services (HHS) holds the authority to declare public health emergencies with potential national security implications related to COVID-19. Under such circumstances, the Food and Drug Administration (FDA) may issue an EUA for drugs and biological products, contingent upon meeting specific statutory requirements outlined in Section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
These requirements include:
- Serious or Life-Threatening Disease: The agent, in this case, the SARS-CoV-2 virus and its variants, must be capable of causing a serious or life-threatening disease.
- Efficacy Evidence: FDA must have reasonable belief, based on scientific evidence, that the product is effective in preventing, diagnosing, or treating the disease caused by SARS-CoV-2, or in mitigating a disease caused by an FDA-regulated product used to diagnose, treat, or prevent such disease.
- Benefit-Risk Analysis: The known and potential benefits of the product, when used for diagnosing, preventing, or treating the identified disease, must outweigh the known and potential risks.
- Lack of Alternatives: There should be no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating the disease.
When these criteria are met, the FDA can grant an EUA for unapproved medical products or unapproved uses of approved medical products to be employed in emergencies. The FDA plays a pivotal role in providing regulatory guidance to COVID-19 vaccine manufacturers, ensuring that data substantiates the balance between benefits and risks, while maintaining product quality and consistency.
FDA Guidance for Industry Related to COVID-19 Vaccines, Including Modified COVID-19 Vaccines
The FDA has consistently evolved its guidance to accommodate the changing landscape of the pandemic. The FDA Guidance for Industry, “Emergency Use Authorization for Vaccines to Prevent COVID-19,” first issued in October 2020 and last updated in March 2022, outlines a comprehensive approach to Chemistry, Manufacturing, and Controls (CMC), nonclinical, and clinical data required to support the safety and efficacy of modified monovalent vaccines to address emerging SARS-CoV-2 variants.
Regarding clinical data, the guidance initially recommended clinical evaluation of modified monovalent vaccines. However, the FDA’s position has evolved as more data has become available concerning SARS-CoV-2 variants and their corresponding vaccines. A prime example of this evolution is the authorization of the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula), which did not rely on clinical studies of the new formulation. Instead, the FDA leveraged the extensive experience gained from the Pfizer-BioNTech COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and BA.4/BA.5), alongside CMC and preclinical data submitted as part of the EUA request.
This collective experience, coupled with rigorous data analysis, has established a favorable benefit-risk profile for the use of Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) under EUA. It underscores the adaptability and pragmatism of regulatory agencies in responding to the ever-changing landscape of the COVID-19 pandemic while ensuring the safety and efficacy of vaccines.
FDA Review of Clinical Effectiveness and Safety Data
Overview of Clinical Studies
In our continued effort to ensure the safety and efficacy of COVID-19 vaccines, the FDA has conducted a comprehensive review of clinical effectiveness and safety data for the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) for individuals aged 6 months through 11 years. The data presented here builds upon previous studies conducted with the Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) and the Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5), as these vaccines share the same manufacturing process.
Effectiveness of Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula)
The effectiveness of the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in individuals aged 6 months through 11 years is derived from multiple sources:
- Efficacy of 2-Dose Primary Series of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) in participants aged 16 years and older.
- Efficacy of 2-Dose Primary Series of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) in participants aged 12 through 15 years.
- Efficacy of 2-Dose Primary Series of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) in participants aged 5 through 11 years.
- Immunogenicity of 2-Dose Primary Series of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) in participants aged 5 through 11 years.
- Effectiveness of 3-Dose Primary Series of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) in participants aged 6 months through 4 years.
- Immunogenicity of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) Booster Dose following Pfizer-BioNTech COVID-19 Vaccine (Original Monovalent) Primary Series in participants aged 5 through 11 years.
- Immunogenicity of the Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) Booster Dose following Primary Vaccination with Another Authorized or Approved COVID-19 Vaccine (Original monovalent).
- Immunogenicity of Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) Administered as a Booster (Fourth Dose) in Individuals aged 6 months through 4 years.
- Effectiveness of a Single Dose of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) in Individuals with Evidence of Prior SARS-CoV-2 Infection.
Detailed evidence supporting these points can be found in sections 6.2 and 6.3 of the FDA Review Memorandum Dated April 18, 2023.
For individuals with certain types of immunocompromise aged 6 months through 11 years, the effectiveness of the Pfizer-BioNTech COVID-19 Vaccine three-dose series is inferred from the immunogenicity of the third primary series dose. This inference is based on the evidence presented in the August 12, 2021, Review Memorandum.
Additional data supporting the effectiveness of extra doses of Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in immunocompromised individuals aged 6 months through 11 years is available in the FDA Review Memorandum Dated April 18, 2023. This data includes:
- Immunogenicity of a Fourth Dose of Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) after Completion of Primary Vaccination with 3 doses of the Pfizer-BioNTech COVID-19 Vaccines in Individuals aged 6 months through 4 years.
- Immunogenicity of a Single Booster Dose of Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) Administered at Least 2 months after Completion of Primary Vaccination or Receipt of the Most Recent Booster Dose with an Authorized or Approved Monovalent COVID-19 Vaccine in Individuals aged 5 through 11 Years.
- Effectiveness of Additional Doses Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) in Immunocompromised Individuals.
For detailed information on these studies, please refer to the respective sections of the FDA Review Memorandum Dated April 18, 2023.
In summary, the effectiveness data from previous Pfizer-BioNTech COVID-19 vaccines (Original monovalent and Bivalent) are highly relevant to the Pfizer BioNTech COVID-19 Vaccine (2023-2024 Formula) because they share the same manufacturing process. The totality of evidence from clinical trials, including efficacy and effectiveness data, and immunogenicity data supports the use of Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in individuals aged 6 months through 11 years.
Furthermore, preclinical data indicates that Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) induces higher neutralizing antibody titers against XBB sublineages, including XBB.1.5, XBB.1.16, XBB.1.16.1, and XBB.2.3 when compared to the Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5).
Given the urgency of addressing the evolving COVID-19 situation and the need for a vaccine closely matched to circulating variants, the FDA has issued an Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) based on the relevant safety and effectiveness evidence from previously authorized and currently approved Pfizer-BioNTech COVID-19 vaccines, all manufactured using the same process. Supportive preclinical animal data for the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) further reinforces this decision.
The safety of Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in individuals aged 6 months through 11 years has been rigorously assessed using a variety of data sources.
Safety data from clinical studies evaluating both primary and booster vaccination with Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) have been thoroughly examined. Additional safety follow-up data have been reviewed in support of the Emergency Use Authorization. Detailed information on these studies can be found in the EUA Memorandum Dated May 17, 2022, and the clinical memorandum supporting the approval of STN 125742/276.
Safety data from clinical studies assessing booster vaccination with Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5), as well as a booster dose of bivalent vaccine (Original and Omicron BA.1), have also been examined in detail. Refer to the EUA memorandum dated March 14, 2023, and the EUA memorandum dated August 31, 2022, for comprehensive reviews of these studies.
Review of postmarketing safety data has indicated a similar safety profile between the Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) and the Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5). While the most current worldwide and U.S. administration data are not known, estimated distribution data provides an indicator of vaccine exposure.
As of June 18, 2023, approximately a significant number of doses of Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) and Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5) have been shipped worldwide since respective vaccine authorization dates. In the U.S., more than 366 million doses of the original Pfizer-BioNTech COVID-19 Vaccine (Original monovalent) have been administered, along with over 36 million doses of the Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5). Of these, more than 3 million doses have been given to individuals aged 6 months through 4 years, and more than 22 million doses have been administered to individuals aged 5 through 11 years.
In recipients of all doses of Pfizer-BioNTech COVID-19 vaccines among children aged less than 6 months to less than 12 years, the most frequently reported preferred terms (PTs) to the Vaccine Adverse Event Reporting System (VAERS) include administrative issues such as incorrect dose administered, product preparation issues, and others like pyrexia, vomiting, headache, and fatigue. The Sponsor is actively conducting additional safety-related post-authorization/postmarketing studies, including assessments of known serious risks and unexpected serious risks.
The FDA’s assessment of the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) takes into account the known and potential benefits and risks, based on accumulated data from all doses of Pfizer-BioNTech COVID-19 vaccines to date. This assessment supports the conclusion that the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) has a favorable benefit-risk profile, making it suitable for use in individuals aged 6 months through 11 years. The proposed updated vaccination schedule is informed by this assessment and aims to address the ongoing public health need for COVID-19 vaccination.
Benefit-Risk in the Context of the Proposed EUA for Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in Individuals 6 Months of Age and Older
In this chapter, we will delve into a comprehensive discussion of the benefits, risks, and uncertainties surrounding the proposed Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in individuals aged 6 months and older. This vaccine, which builds upon the lessons learned from previous iterations, aims to provide enhanced protection against the ever-evolving SARS-CoV-2 virus and its variants.
Discussion of Benefits, Risks, and Uncertainties
The Ongoing Impact of COVID-19
COVID-19, caused by the SARS-CoV-2 virus, has wreaked havoc globally, with the United States bearing a significant burden, tallying over 104 million cases and 1.1 million deaths as of this writing. This viral adversary has displayed remarkable adaptability, giving rise to various strains, including Beta, Delta, Omicron BA.1, and more recently, Omicron BA.5, BQ.1.1, XBB.1.5, and other Omicron sublineages. The existing arsenal of COVID-19 treatments, encompassing antiviral medications, immune modulators, and convalescent plasma, demonstrates its greatest efficacy in managing mild to moderate cases, leaving those with severe disease inadequately served. Moreover, these treatments may fall short in preventing complications such as the enduring effects of COVID-19, often referred to as “long COVID.”
The Role of Vaccines in Controlling the Pandemic
Amid this challenging landscape, FDA-approved and authorized vaccines have emerged as a crucial tool in the battle against COVID-19. For individuals aged 6 months and older, the currently authorized vaccines include mRNA-based vaccines from Moderna and Pfizer-BioNTech, along with an adjuvanted protein subunit vaccine from Novavax (for those aged 12 and older). These vaccines initially exhibited impressive effectiveness of up to 90 to 95% against symptomatic disease when based on the original (ancestral) strain of SARS-CoV-2.
The Challenge of Variants and Waning Immunity
However, the relentless evolution of SARS-CoV-2 variants and the natural waning of individual immunity have led to a reduction in vaccine effectiveness over time. Studies conducted in various countries have illuminated this phenomenon, with vaccine efficacy against symptomatic disease declining faster than that against severe disease. Booster doses, based on the original strain, have been successful in restoring a degree of protection against both serious and symptomatic disease in the face of these viral variants.
The Emergence of Bivalent Vaccines
Recognizing the need for updated vaccines to counter the evolving threat, Pfizer-BioNTech and Moderna embarked on developing mRNA booster vaccines tailored to the Beta, Delta, and Omicron BA.1 variants. Although these booster vaccines were evaluated and found effective, their deployment in the U.S. was deferred due to the rapid emergence of new SARS-CoV-2 variants. However, following the emergence of the Omicron variant and its sublineages, notably BA.4/BA.5, in November 2021, evidence suggested that bivalent vaccines (Pfizer-BioNTech COVID-19 Vaccine, Bivalent, and Moderna COVID-19 Vaccine, Bivalent) provided enhanced protection compared to the original monovalent vaccines. Consequently, on August 31, 2022, FDA authorized the use of these bivalent vaccines for booster doses in individuals aged 12 or 18 and older, respectively. Subsequently, in April 2023, these bivalent vaccines were authorized for all doses in individuals aged 6 months and older, ushering in significant changes in vaccine recommendations and usage.
The Need for Ongoing Adaptation
While the bivalent (Original and Omicron BA.4/BA.5) COVID-19 vaccines have offered improved protection against Omicron sublineages, including BA.4/BA.5, it is important to note that their effectiveness appears to wane over time. This suggests that an updated vaccine composition, more closely aligned with currently circulating Omicron sublineages, is warranted to sustain long-term protection.
Safety and Immunogenicity
Assessing the safety and effectiveness of the Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula), we draw upon data from nonclinical studies and comparisons with the bivalent counterpart. These studies indicate higher neutralizing antibody responses when the 2023-2024 Formula is administered to both vaccine-naïve and vaccine-experienced laboratory animals, particularly against currently circulating XBB-related sublineages. In immunocompetent and immunocompromised individuals aged 6 months through 11 years, it is reasonable to expect that this new formula will enhance immune responses and clinical protection against SARS-CoV-2 variants, including the prevailing Omicron sublineages, when compared to the previous bivalent vaccine.
Consideration of Adverse Effects
Additional doses of the vaccine, whether primary series or booster shots, may come with transient local and systemic symptoms, consistent with previous administrations. Notably, myocarditis has emerged as an uncommon side effect associated with mRNA-based COVID-19 vaccines. Data from the FDA Biologics Effectiveness and Safety (BEST) System reveals varying rates of myocarditis or pericarditis, particularly among males aged 18-25 years. It is important to underscore that the majority of cases have been mild and transient.
Continuous monitoring of adverse reactions and emerging safety concerns post-EUA is paramount. Both passive and active surveillance systems will be employed to swiftly detect and address any unexpected developments.
Table 3 provides a summarized view of the benefit-risk considerations in a standard FDA format, facilitating a comprehensive assessment of the proposed EUA for Pfizer-BioNTech COVID-19 Vaccine (2023-2024 Formula) in individuals aged 6 months and older. This holistic analysis aims to guide regulatory decisions and public health strategies in the ongoing battle against COVID-19.
reference link : https://www.fda.gov/media/172019/download