How many FDA approved Combination vaccine are there?

Overview of Combination Vaccines

Definition and Types of Combination Vaccines
Combination vaccines are medical products that incorporate more than one immunizing antigen within a single dose, thereby protecting individuals against multiple infectious diseases with one injection. They can be broadly categorized into two major types:
• Multivalent vaccines that contain several serotypes or strains of the same pathogen (for example, pneumococcal conjugate vaccines such as Prevnar 13 and Prevnar 20, which include polysaccharides from 13 and 20 pneumococcal serotypes, respectively).
• Multi‑disease vaccines that combine antigens from entirely different pathogens into a single formulation (for example, pediatric vaccines such as those combining diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b, and hepatitis B).
In addition, there exist live attenuated combination vaccines (e.g., the MMR vaccine for measles, mumps, and rubella, or tetravalent dengue vaccines like Dengvaxia) that are designed to induce immunity against multiple viral serotypes concurrently.
At the molecular level, many of these combination vaccines use conjugate technology—that is, coupling poorly immunogenic polysaccharides to immunogenic carrier proteins—to enhance the immune response, a design particularly used in vaccines for encapsulated bacteria.

Advantages of Combination Vaccines
Combination vaccines have been introduced for several important reasons that benefit clinical practice and public health:
• They reduce the number of injections required to achieve wide coverage against multiple diseases, thereby improving patient compliance and reducing the pain and anxiety especially among infants and children.
• Fewer appointments are necessary, which cuts down on logistical burdens for both providers and health systems and helps lower overall healthcare costs.
• In many settings, combination vaccines help streamline immunization schedules and support higher vaccination coverage rates, which in turn contributes to herd immunity in the population.
• They also reduce storage and supply‐chain requirements since fewer vials or syringes are needed, while simultaneously trading off minimal interference among components when properly formulated.
• From an immunological angle, by presenting multiple antigens in one dose, these vaccines can stimulate broad protective responses—although it is crucial that each component is given at the optimal dose to avoid antigenic interference.

FDA Approval Process

Criteria for Vaccine Approval
The U.S. Food and Drug Administration (FDA) regulates vaccines under rigorous standards to ensure that they are both safe and effective before they are introduced to the public. For combination vaccines, the FDA has to consider not only the safety and immunogenicity of each individual antigen but also the potential interactions between them.
Key FDA criteria include:
• Evidence from well‑controlled clinical trials demonstrating that the vaccine generates appropriate immune responses (immunogenicity data) and clinical benefit, whether measured through a surrogate endpoint or clinical outcome.
• Proof that combining antigens does not diminish efficacy compared to when the antigens are given separately, which is known as noninferiority testing.
• Demonstration of an acceptable safety profile in both pre-licensure (Phase I–III) and post-marketing (Phase IV) studies—this is particularly critical for combination vaccines since any unexpected adverse interactions between antigens need to be ruled out.
• Robust quality and consistency in manufacturing practices are required to ensure that each dose meets predetermined potency and purity standards.
• The overall risk-benefit profile must be favorable; meaning that the public health benefits conferred by reduced disease burden and improved compliance must outweigh potential adverse effects.

Steps in the FDA Approval Process
The process to gain FDA approval is multi‐layered and can be summarized in several key steps, which are essentially similar for combination vaccines as for monovalent ones, albeit with some additional considerations:
• Preclinical Testing: Combination vaccines undergo extensive in‑vitro and in‑vivo studies to evaluate safety and immunogenicity before any human studies begin. Early-stage research also looks at potential interactions between antigens when combined.
• Phase I Clinical Trials: A small number of healthy volunteers are enrolled to determine safety, optimal dosing, and preliminary data on immune response. For combination vaccines, these studies also assess whether one component interferes with another.
• Phase II Clinical Trials: These trials enroll a larger group of subjects to refine dosing, further evaluate the fallouts of combining antigens, and assess initial immunogenicity endpoints.
• Phase III Clinical Trials: Large-scale trials are conducted to verify the vaccine’s effectiveness, noninferiority compared to separate injections if applicable, and to firmly establish the safety profile. The trials are usually randomized, double-blind, and controlled.
• Regulatory Submission and Advisory Committee Review: The manufacturer submits a Biologics License Application (BLA) including detailed data from all preclinical and clinical studies. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) reviews the data and offers recommendations.
• Inspection and Post-Marketing Surveillance: Once approved, manufacturing facilities are inspected for compliance with good manufacturing practices (GMP), and the vaccine enters the market with active post-marketing monitoring such as through the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD).
This comprehensive process ensures that every approved vaccine, including combination formulations, meets the high standards required for public use.

List of FDA Approved Combination Vaccines

Current Approved Vaccines
Based on the synapse sources provided and our review of structured drug application records, the current list of FDA‑approved combination vaccines includes the following (each of which has undergone the FDA_CBER review process):

1. CAPVAXIVE – Developed by Merck Sharp & Dohme LLC, this combination vaccine was approved on June 17, 2024. It is administered intramuscularly and has a trade name “CAPVAXIVE.” This vaccine represents a modern approach to combining antigens aimed at reducing the number of injections required for immunization.
2. Vaxneuvance – Manufactured by Merck Sharp & Dohme Corp., Vaxneuvance was approved on July 16, 2021. It is designed as a pneumococcal conjugate vaccine that includes multiple serotypes to provide broad coverage against pneumococcal infections.
3. Prevnar 20 – Produced by Wyeth Pharmaceuticals LLC, this pneumococcal conjugate vaccine, which covers 20 serotypes, was approved on June 08, 2021. Its multi-antigen composition places it in the combination vaccine category because it is formulated by linking polysaccharides from different serotypes to a carrier protein.
4. Quadracel – Approved on March 24, 2015, Quadracel by Sanofi Pasteur, Inc. is a combination vaccine covering diphtheria, tetanus, acellular pertussis, and inactivated poliovirus (DTaP-IPV). Its approval came after demonstrating that the combined formulation is noninferior to separate injections.
5. Dengvaxia – This is a live attenuated, tetravalent dengue vaccine developed by Sanofi Pasteur and approved on May 01, 2019. Although it targets four serotypes of dengue virus, its formulation is considered combination due to the inclusion of multiple, distinct viral components in one dose.
6. Flublok – Developed by Protein Sciences Corp., Flublok is a recombinant influenza vaccine that was approved on January 16, 2013. It is designed to stimulate immunity against influenza with antigens produced without the use of eggs, and its multivalent formulation qualifies it as a combination vaccine.
7. Kinrix – Manufactured by GlaxoSmithKline LLC, Kinrix is an FDA‑approved pediatric combination vaccine (DTaP-IPV) that was approved on June 24, 2008. It combines antigens for diphtheria, tetanus, acellular pertussis, and inactivated poliovirus.
8. Prevnar 13 – Also produced by Wyeth Pharmaceuticals LLC, Prevnar 13 is a pneumococcal conjugate vaccine covering 13 serotypes and was approved on February 24, 2010. Like Prevnar 20, its conjugate formulation makes it a combination vaccine (linking different polysaccharides with a carrier protein).
9. Vaxelis – Approved on December 21, 2018, by the FDA_CBER with the application number 125563_001 by MSP Vaccine Co., Vaxelis is a hexavalent vaccine that protects against six diseases (DTaP-IPV-Hib-HepB). It represents one of the most comprehensive pediatric combination vaccines available.
10. Menquadfi – Lastly, Menquadfi, developed by Sanofi Pasteur, received FDA approval on April 23, 2020, under application number 125701_001. It is a meningococcal conjugate vaccine that combines multiple antigens to protect against various serogroups of Neisseria meningitidis.

When taken together, these 10 vaccines have been approved by the FDA and represent a variety of combination approaches—ranging from toxoid-based formulations for childhood diseases to conjugate vaccines that protect against pathogens with multiple serotypes. It is important to note that further approvals (or label expansions) may occur as manufacturers continue to improve upon and combine antigens for better public health outcomes.

Historical Approvals and Changes
The evolution of combination vaccines in the U.S. has been both dynamic and responsive to emerging public health needs. For decades, the concept of combining vaccines came to the fore with early formulations designed to protect against diphtheria, tetanus, and pertussis (the DTP vaccine).
• Early combination vaccines were developed empirically, with the primary goal of reducing the total number of injections administered to infants and children.
• Over the years, as scientific understanding of immunologic interactions improved, the FDA began to require that the combined product be tested directly rather than relying on data from separately administered antigens. This has led to more rigorous clinical studies in Phase II and Phase III clinical trials.
• Modern pediatric combination vaccines such as Quadracel and Vaxelis were designed not only to simplify immunization schedules but also to improve immune responses and reduce adverse events compared with sequential individual injections.
• Pneumococcal conjugate vaccines—Prevnar 13, Prevnar 20, and Vaxneuvance—evolved from earlier polysaccharide vaccines and are now considered combination vaccines because they couple multiple serotype-specific antigens to protein carriers.
• The live attenuated Dengvaxia represents another branch of combination vaccine technology aimed at tackling a complex viral disease with multiple serotypes in a single formulation.
Each of these approvals has built on previous experiences. For instance, the transition from DTaP-based products that only combined a handful of antigens to hexavalent vaccines like Vaxelis highlights a historical trend toward ever-more comprehensive products that continue to face scrutiny about interference, dosing, and immunogenicity.
Thus, a review of historical data and regulatory submissions suggests that while combination vaccines have long been part of the immunization landscape, it is in the past 15–20 years that the FDA has provided formal approval for products that are truly “combination” in nature by incorporating multiple independent immunogens into a single preparation.

Impact and Considerations

Public Health Impact
Combination vaccines have transformed immunization programs in the United States and globally by simplifying the protective regimen and ensuring that broad coverage is achieved with fewer injections per patient.
• By reducing the number of injections, these vaccines improve patient and caregiver compliance, particularly in pediatric settings where multiple visits can be a deterrent to complete immunization courses.
• Combination vaccines such as the pneumococcal conjugate products (Prevnar 13, Prevnar 20, and Vaxneuvance) have contributed to dramatic reductions in invasive pneumococcal disease and pneumonia, largely by establishing herd immunity in vulnerable populations.
• Multi-disease vaccines also lessen the administrative burden on health systems by reducing clinic visits and lowering the number of single-use vaccine vials that need to be stored and managed, thereby optimizing supply chain efficiencies and reducing costs.
• The public health benefits are not solely restricted to cost and compliance. Combination vaccines have been shown to contribute to overall reductions in disease outbreaks by ensuring that higher proportions of the population are immunized against several infectious agents simultaneously.

Safety and Efficacy
Each FDA-approved combination vaccine has undergone comprehensive evaluation through multi‑phase clinical trials that address both safety and immunogenicity. These studies typically compare the immune response elicited by the combination product to that of the individual vaccines administered sequentially.
• For example, studies on Quadracel have demonstrated that the immune responses to diphtheria, tetanus, pertussis, and poliovirus antigens in the combination product are noninferior to those observed when the vaccines are administered separately.
• Similarly, Vaxelis underwent rigorous clinical testing to assess its performance as a hexavalent vaccine, and the results confirmed that it is capable of eliciting robust immune responses to all six component antigens in a manner comparable to when these antigens are given as standalone injections.
• The safety profile of each of these products is continuously monitored both before and after regulatory approval. Post-marketing surveillance networks such as VAERS and VSD have been instrumental in detecting rare adverse events, ensuring that any emerging safety signals are promptly evaluated.
• Moreover, the FDA’s insistence on extensive Phase III trials for combination vaccines, which often include thousands of subjects, helps to ensure that even rare side effects are captured and analyzed appropriately.
In terms of efficacy, the multipronged immune response from combination vaccines helps establish a solid protection barrier. The combined antigens not only stimulate humoral responses (antibodies) but also cellular immunity, which is critical in preventing diseases that can evolve rapidly or exist in multiple serogroups/serotypes.

Challenges and Limitations
Despite their many public health benefits, combination vaccines also present several challenges:
• Antigenic Interference: One of the most discussed challenges is the potential for one vaccine component to interfere with the immune response to another. This phenomenon is known as antigenic interference. Although clinical trials are designed to detect such issues, there remains the potential for subtle effects that might only become apparent in larger post-marketing studies.
• Complex Manufacturing Processes: Combining several antigens into one vaccine poses considerable manufacturing challenges. Each antigen must be produced under strict conditions, and the final product must maintain consistency across production batches. Ensuring reproducibility and stability of vaccine components remains an ongoing challenge, impacting cost and availability.
• Regulatory Hurdles: Because combination vaccines must demonstrate not only the safety of each individual component but also the absence of negative interactions among them, the regulatory submission becomes more data‑intensive and complex. This can lengthen the approval process and increase development costs.
• Public Perception: While combination vaccines simplify immunization schedules, they may also contribute to vaccine hesitancy for some individuals who worry about “overloading” the immune system with multiple antigens at one time. Addressing these concerns requires transparent communication of safety data and the scientific rationale behind combination formulations.
• Evolving Pathogen Profiles: As pathogens evolve (for instance, changes in circulating serotypes), combination vaccines may need to be updated to remain effective—this is seen with pneumococcal vaccines. Regulatory pathways must accommodate such changes, which sometimes requires re‑evaluation of the combined formulation’s performance.

Conclusion
In summary, combination vaccines are an essential element of modern immunization strategies, as they combine multiple antigens in a single preparation to improve coverage rates, enhance patient compliance, and reduce the burden on healthcare systems. The FDA approval process for these vaccines is rigorously structured to address the efficacy, safety, and manufacturing complexities unique to multi-antigen formulations. A review of the structured drug applications from synapse indicates that there are currently 10 FDA‑approved combination vaccines. These include products such as CAPVAXIVE, Vaxneuvance, Prevnar 20, Quadracel, Dengvaxia, Flublok, Kinrix, Prevnar 13, Vaxelis, and Menquadfi, each reflecting decades of iterative improvements.
From a general perspective, combination vaccines have made a significant public health impact by simplifying vaccination schedules and enabling broader protection with fewer injections. Specifically, the FDA’s comprehensive review process ensures that each vaccine is as safe and effective when administered as part of a combination as it would be separately. On a more specific level, each of the 10 FDA-approved vaccines mentioned has been tested through robust Phase I–III trials and monitored post-approval, meaning that vaccine developers have successfully addressed concerns of antigenic interference and manufacturing consistency. Finally, from a general standpoint, while challenges remain—particularly in areas of manufacturing complexity, regulatory updates due to pathogen evolution, and public perceptions—the overall benefits of combination vaccines continue to outweigh the limitations, making them a cornerstone of preventive medicine in the U.S.
This detailed evaluation underscores that approximately 10 combination vaccines have earned FDA approval, and it is the combination of scientific rigor, regulatory diligence, and public health necessity that drives ongoing innovation in this field.