What Combination vaccine are being developed?

Introduction to Combination Vaccines

Definition and Purpose
Combination vaccines are formulations that incorporate two or more antigenic components—be they proteins, polysaccharides, or nucleic acids—in a single product. The primary purpose of these vaccines is to induce a protective immune response against multiple pathogens (or multiple distinct antigens of a single pathogen) simultaneously, thereby reducing the number of injections required and increasing patient compliance. By delivering a mixture of immunogens in the same formulation, combination vaccines reduce the logistical burden on healthcare systems, improve storage efficiency, and streamline immunization schedules—for example in pediatrics, where parents and clinicians greatly appreciate fewer needle-stick events. In addition to improved administration convenience, combination vaccines also have the potential to generate broader immune responses when the vaccine components are carefully formulated to avoid immune interference – a sometimes observed phenomenon where one antigen may suppress the immune response to another. Furthermore, combination vaccines have been developed to address the rising complexity of immunization programs, especially when national vaccination schedules evolve to cover many diseases simultaneously, such as diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib), and hepatitis B. These formulations represent the confluence of advances in immunology, formulation chemistry, and vaccine production technology.

Historical Development
The idea of combining multiple vaccines into one formulation is not new. Historically, the development of combination vaccines began with early approaches to deliver antigens against diphtheria, tetanus, and pertussis concurrently, such as formulations based on the childhood DTP vaccine, which provided the obvious advantage of fewer injections. Over the decades, further antigens were added—resulting in the birth of pentavalent and hexavalent vaccines that combine DTaP (diphtheria, tetanus, and acellular pertussis) with additional antigens such as hepatitis B, inactivated polio vaccine (IPV), and Hib. Early combination vaccines started with the “mixing” of individual monovalent vaccines immediately before administration. Over time, advances in conjugation technologies, adjuvant optimization, and recombinant DNA methods allowed the antigens to be co-formulated in a stable, pre-mixed product that maintained its potency, safety, and immunogenicity. These historical developments also paved the way for more sophisticated platforms—such as mRNA-encoded antigen vaccines and virus-like particles (VLPs)—that have recently been adapted to combination approaches, especially in response to emerging infectious threats such as respiratory viruses. In designing combination vaccines, researchers have constantly strived to balance immunogenicity against potential immune interference, a challenge that has driven the need for advanced testing and validation methodologies during vaccine development.

Current Combination Vaccines in Development

Leading Candidates
Currently, several innovative combination vaccine candidates are under development, each reflecting the diversity of the vaccine technologies available today. For instance, a notable candidate represents a combination RNA vaccine that encodes both a Fusion (F) protein (or its fragment) derived from viruses of the Paramyxoviridae family and a Hemagglutinin (HA) protein (or its fragment) derived from viruses of the Orthomyxoviridae family. This candidate has been documented in multiple patents and is being developed by companies such as CureVac SE. The approach leverages the ability of messenger RNA platforms to rapidly manufacture vaccine components and stands out as an effort to protect populations against respiratory diseases like respiratory syncytial virus (RSV) in combination with influenza.

Other prominent combination vaccines in development target pediatric diseases. Researchers have developed and are refining combination vaccines that merge antigens for diphtheria, tetanus, and pertussis with inactivated poliovirus, Hib conjugate, and hepatitis B antigens. Examples include the hexavalent vaccine formulations, which have evolved over several generations—from the early versions that required reconstitution to the most recent ready-to-use, fully liquid products that have improved safety profiles and ease of administration. In addition, some combination vaccine candidates are specifically tailored for animal health. An example is the combination vaccine directed at swine diseases: a PCV2 (porcine circovirus type 2) antigen is combined with a pre-formed antigen/adjuvant complex featuring a Mycoplasma hyopneumoniae (M. hyo) antigen adsorbed to an aluminum hydroxide adjuvant. This vaccine candidate is being developed to address PCV2 and M. hyo infections in swine.

In the realm of COVID-19 vaccine development, there is also growing interest in mix-and-match strategies. Companies such as Moderna and Pfizer are exploring heterologous vaccination regimens where different vaccine platforms (for example, an adenoviral vector vaccine paired with an mRNA vaccine) are combined to boost immune response while increasing manufacturing flexibility. Moderna, for example, has expressed interest in combining a COVID-19 vaccine with seasonal influenza vaccines to produce a dual-protection regimen that could simplify prophylaxis for respiratory pathogens, setting the stage for a potential triple combination that might later include RSV protection as well. The heterologous approaches allow for customized booster regimes that blend the strengths of different vaccine platforms without necessarily requiring the development of a completely single formulation.

Another innovative approach is represented by newly functional multiply mixed vaccines, which involve combining several conventional vaccine formulations into one product by a process of “mix and match” research and development. Although these products involve more traditional antigens, they are designed to produce a therapeutic effect beyond prophylaxis, with the idea that such combinations may be beneficial not only for disease prevention but also for treatment. Moreover, combination strategies are being investigated for use in combating fungal infections such as candidiasis. Researchers are examining multicomponent glycoconjugate vaccines that could elicit protective responses against pathogens like Candida spp., although these are still in the early research phase due to challenges with antigen variability and immunotolerance.

Target Diseases and Pathogens
The target diseases and pathogens for combination vaccines being developed span a very wide spectrum. In the pediatric context, the current combination vaccines in development primarily target childhood diseases such as diphtheria, tetanus, pertussis, polio, Hib, and hepatitis B. These diseases have historically been bundled because of their vaccine-preventable nature and the benefits of fewer injections for infants and young children.

Beyond the established pediatric pathogens, recent developments focus on respiratory diseases. For example, the combination RNA vaccine candidate encodes antigens for RSV and influenza, thereby targeting the major respiratory pathogens that cause significant morbidity among both children and older adults. In addition, the potential mix of COVID-19 and influenza antigens is aimed at addressing the dual burden of a pandemic virus alongside seasonal influenza strains, which often circulate simultaneously during colder months.

For animals, particularly in the agricultural sector, combination vaccines target pathogens that affect production animals. The swine combination vaccine combining PCV2 and M. hyo is strategically designed to reduce the economic and health burdens associated with respiratory and systemic infections in pigs.

Researchers are also investigating combination vaccines for emerging infections and complex diseases. In oncology, combination vaccine approaches are being developed to simultaneously target multiple tumor-associated antigens, although the regulatory and safety challenges are significant. Similarly, combination strategies against chronic infections such as HIV and tuberculosis are being explored, wherein multi-antigen formulations may yield superior protective responses compared to monovalent vaccines. Furthermore, combination vaccines may also incorporate components addressing non-infectious conditions, including therapeutic vaccines for cancer or even immunotherapies for autoimmune conditions, where the rational combination of immunogens might lead to better clinical outcomes.

Research and Development Methodologies

Vaccine Formulation and Testing
The formulation of combination vaccines requires advanced methodologies that ensure each component retains its immunogenicity over time while not interfering with the immune responses elicited by other components. One of the pioneering techniques involves the use of RNA-based platforms in which multiple antigen-encoding mRNAs are formulated into a single lipid nanoparticle-based vaccine. This method not only speeds up development times but allows for rapid re-engineering in response to antigenic drift in viral pathogens. Such RNA formulations need to be optimized for stability, efficient antigen expression, and minimal reactogenicity.

Another important formulation approach is the conjugate vaccine technology. In this strategy, polysaccharide antigens (which are typically poorly immunogenic on their own) are chemically linked to protein carriers to invoke a T-cell–dependent immune response. This technology has been widely applied in pediatric vaccines such as those against Hib, pneumococcus, and meningococcus. The conjugation methods, including various linker strategies and purification processes, are under continuous refinement to enhance batch-to-batch consistency and vaccine potency while also addressing immunological interference issues when combined with other vaccine components.

Furthermore, formulation research has expanded into novel delivery systems such as microneedle patches and nanoparticle-based systems. Microneedle patches not only offer an alternative delivery route that may improve vaccine uptake and compliance but also potentially stabilize vaccines outside of stringent cold-chain requirements. The integration of adjuvants into combination vaccine formulations is another crucial area. Traditional adjuvants, such as aluminum salts (alum), have been used to boost the immune response; however, the interplay between different adjuvants and multiple antigens must be carefully balanced to avoid detrimental effects, such as reduced antibody titers for a specific component. Advanced adjuvant systems like AS04 (an alum plus MPL formulation) are sometimes incorporated to enhance the immunogenicity of complex vaccine formulations without causing excessive reactogenicity.

Preclinical testing methods for combination vaccines include in vitro assays that characterize antigen expression and immune cell activation, animal models that can help predict human responses, and even human challenge models for certain infections—for example, in Shigella vaccine research. Additionally, systems serology and systems biology approaches are increasingly employed to profile immune responses comprehensively; these methods use high-throughput sequencing, proteomics, and metabolomics to identify immune correlates of protection.

Clinical Trial Phases and Challenges
Clinical testing of combination vaccines proceeds through the standard phases: Phase I (safety and immunogenicity in a small group), Phase II (dosage determination and further safety assessments), and Phase III (large-scale efficacy studies). However, combination vaccines face unique challenges during clinical trials. One crucial challenge is ensuring that each antigen component independently elicits a robust immune response even when administered as part of a combination product. Sometimes, immune interference may lead to reduced titers for one or more components; for example, several studies have reported that the Haemophilus influenzae type b (Hib) component’s antibody response could be diminished when combined with acellular pertussis antigens. In such cases, formulation adjustments—such as modifying antigen doses or reformulating adjuvant combinations—are often necessary to maintain efficacy.

Adaptive trial designs have been increasingly applied to combination vaccines. These designs allow investigators to modify aspects of the trial—such as dosing regimen, interval between doses, or sample stratification—in real-time as interim data are evaluated. This flexibility is particularly useful for combination vaccines because it enables researchers to quickly address issues of immune interference or reactogenicity without having to start a new trial from scratch. Moreover, rigorous safety assessments are critical. Large Phase III trials and post-licensure Phase IV studies are designed to capture both common and rare adverse events to ensure that the addition of multiple antigens does not introduce new safety risks.

Another challenge in clinical evaluation is demonstrating non-inferiority of the combination vaccine compared with its individual components when given separately. Regulatory agencies like the US FDA and EMA require evidence that the immune responses to each antigen in the combination product are at least as good as those elicited by the monovalent vaccines. This often involves detailed immunogenicity analyses using validated assays (e.g., ELISA, multiplex immunoassays), as well as carefully designed statistical analyses to confirm that the combination therapy meets predefined thresholds of efficacy. In addition, for novel combination vaccines such as those incorporating RNA components for RSV and influenza, the accelerated development timelines seen during the COVID-19 pandemic have necessitated innovative trial designs that balance speed with rigour.

Impact and Future Directions

Benefits and Potential Challenges
The primary benefits of combination vaccines are evident in their ability to reduce the number of injections needed in immunization schedules, thereby enhancing vaccine coverage and compliance. Fewer clinic visits mean a lower overall burden on healthcare infrastructure and reduced discomfort for patients, which is particularly important in pediatric populations. Cost savings arise not only from the reduced number of vaccine doses but also from the streamlined manufacturing and distribution processes. For example, ready-to-use combination vaccines eliminate the need for reconstitution steps that are both time-consuming and error-prone.

Despite these benefits, there are potential challenges inherent to combination vaccines. One major issue is the risk of immunological interference where the immune response to one antigen can impair or suppress the response to another, as has been observed in some DTaP-based combination vaccines. Moreover, the manufacturing processes for combination vaccines are inherently more complex, requiring strict quality control to ensure that the stability and potency of each component are maintained across production batches. Another challenge arises during clinical development: demonstrating that the combined product is non-inferior to its individual components necessitates larger sample sizes and more sophisticated adaptive trial designs. Additionally, differences in the storage, handling, and distribution profiles of multiple vaccine components can further complicate the logistical aspects of deploying combination vaccines in real-world settings, particularly in low- and middle-income countries.

For newer platforms such as RNA-based combination vaccines, while there is significant promise in terms of rapid development and flexibility, long-term safety data and durability of immune responses are still being collected. Regulatory challenges also persist, including the need for harmonized guidance on evaluating the safety and efficacy of multi-antigen products, especially when novel vaccine technologies are employed alongside more established ones. In the realm of animal vaccines, too, combination formulations must overcome similar issues of potential antigenic interference and manufacturing complexities, though the stakes and timelines may differ from human vaccination programs.

Future Trends in Vaccine Development
Looking ahead, the future of combination vaccines appears promising, driven by advances in vaccine design, formulation, and delivery technologies. One emerging trend is the continued expansion of combination products for respiratory diseases. With seasonal influenza, RSV, and COVID-19 now recognized as major public health concerns, companies are racing to produce vaccines that offer simultaneous protection against multiple respiratory pathogens in a single shot. For example, Moderna’s plans for a combination COVID-19/influenza vaccine, with potential expansion to include RSV antigens, exemplify this approach and could revolutionize adult immunization programs. Such combination vaccines will not only simplify vaccine administration but also potentially offer synergistic immune benefits by stimulating broader-spectrum protection.

Another trend is the continued push for improved formulation technologies, including nanoparticle carriers, microneedle patches, and advanced conjugate approaches. Nanoparticle-based vaccine formulations show promise in protecting the antigens from degradation, targeting delivery to antigen-presenting cells, and modulating the immune response for greater efficacy. Microneedle patches offer the additional benefit of painless administration and simplified storage and distribution logistics, which is particularly advantageous in resource-poor settings. In addition, the development of advanced conjugation techniques is likely to drive the next generation of multivalent pediatric vaccines, as improved carrier proteins and linker strategies help overcome the challenges of antigen interference and yield more consistent immune responses.

From a regulatory perspective, there is also a growing recognition of the need for innovative clinical trial designs and real-time adaptive monitoring systems to evaluate combination vaccines. The integration of systems biology approaches with traditional immunogenicity assays will provide a more detailed understanding of the correlates of protection and help tailor combination regimens more effectively. As computational tools such as machine learning become more prevalent in the analysis of clinical trial data, vaccine developers will be better equipped to predict outcomes and optimize formulations before large-scale production. Furthermore, emerging regulatory frameworks aim to support accelerated pathways for combination vaccines without compromising on safety or long-term efficacy, as evidenced by several emergency use authorizations during the COVID-19 pandemic.

There is also significant momentum in developing combination vaccines outside of the typical infectious disease sphere. Research into prophylactic or therapeutic vaccines for conditions such as cancer, chronic infections (like HIV or tuberculosis), and even fungal infections such as candidiasis is underway. These efforts underscore the broader applicability of combination vaccine strategies, where the goal is to induce robust, multi-faceted immune responses in complex disease contexts. Moreover, as studies continue to demonstrate the economic and health benefits associated with streamlined combination immunization schedules, national and international public health agencies may increasingly recommend—and even mandate—the use of such vaccines.

Conclusion
In summary, the development of combination vaccines represents a dynamic and robust area of research with wide-ranging implications for public and animal health. On the one hand, these vaccines are defined by their capacity to concurrently target multiple pathogens or antigens in a single formulation, a concept that has evolved significantly from early attempts at mixing individual vaccines in the field to the highly engineered products seen today. The historical progression from simple DTP formulations to complex hexavalent vaccines demonstrates the continuous improvement in vaccine safety, immunogenicity, and logistics, addressing critical concerns such as the number of injections and complex immunization schedules.

Currently, leading candidates in the field include innovative RNA-based combination vaccines—such as those encoding RSV Fusion and influenza HA proteins developed by CureVac—as well as recent advancements in combination approaches for pediatric diseases (e.g., DTaP-IPV-Hib-HepB vaccines) and animal vaccines targeting infections in swine (e.g., PCV2/M. hyo vaccines). In the era of COVID-19, heterologous vaccination strategies and mix-and-match regimens are further expanding the boundaries of combination vaccine design by integrating different vaccine platforms to optimize immune responses while offering logistical flexibility.

Research and development methodologies have adapted to these new challenges with advanced formulation techniques that include conjugation methods to link polysaccharide antigens to protein carriers, lipid nanoparticle systems for mRNA delivery, and novel adjuvant systems that minimize immune interference while maximizing immunogenicity. Clinical trial design for these products is evolving as well, with adaptive trials and large-scale immunogenicity assessments aimed at ensuring that each component of the vaccine meets regulatory efficacy and safety standards while also addressing manufacturing complexities.

The impact of combination vaccines is far-reaching: they offer significant benefits such as fewer injections, lower administration costs, improved patient compliance, and more efficient immunization programs. However, challenges remain, including the risk of immune interference, manufacturing scale-up issues, and the need for more comprehensive long-term safety and efficacy data. Looking to the future, trends indicate that combination vaccines will increasingly incorporate multi-pathogen targets, leverage advanced delivery technologies such as microneedle patches, and employ computational and systems biology tools to streamline development and predict immune outcomes. These advances are expected to revolutionize both preventive and therapeutic vaccinations, extending their utility beyond classical infectious diseases to areas like cancer and chronic infections.

In conclusion, the array of combination vaccines under development reflects a concerted effort by researchers, manufacturers, and regulatory bodies to address the complex challenges of modern immunization. By combining multiple antigens into a single formulation through innovative platforms and sophisticated testing methodologies, the next generation of combination vaccines promises to enhance global health outcomes through improved coverage, efficiency, and efficacy. Although technical, clinical, and regulatory hurdles remain, the continuous evolution of vaccine technologies and adaptive clinical strategies offers a very promising outlook for the future of combination immunization strategies.