What are the different types of drugs available for Genetically engineered subunit vaccine?

Overview of Genetically Engineered Subunit Vaccines

Genetically engineered subunit vaccines represent a modern approach in vaccine development that leverages recombinant DNA technology to produce highly purified antigens capable of eliciting protective immune responses while minimizing unnecessary components that can lead to adverse reactions. These vaccines have emerged as a key platform—especially evident during the COVID-19 pandemic—with the goal of ensuring both safety and efficacy in protecting diverse populations.

Definition and Mechanism

Genetically engineered subunit vaccines are composed of one or more antigenic proteins (or fragments thereof) that are crucial for inducing an immune response. Unlike traditional vaccines that may use whole pathogens (attenuated, inactivated, or killed forms), subunit vaccines include only the selected components the immune system targets. This manufacturing strategy is performed via recombinant DNA techniques in various expression systems such as bacteria, yeast, insect cells, or mammalian cells. The resulting proteins are highly purified and, when administered with suitable adjuvants, trigger both humoral and cellular immune responses. In most cases, the primary antigen used is the spike (S) protein of viruses like SARS-CoV-2, which is responsible for receptor binding and membrane fusion, making it an ideal target for neutralizing antibody production. The mechanism generally involves the antigen’s uptake by antigen-presenting cells (APCs), processing into peptides, and presentation via major histocompatibility complexes (MHC), which in turn prime T cells and activate B cells for antibody production. This tailored immune stimulation reduces the risks associated with introducing live pathogens and supports precision vaccine design.

Historical Development and Milestones

The concept of targeting specific antigens dates back to the development of early recombinant vaccines such as the hepatitis B (HBV) vaccine, which was one of the first subunit vaccines approved for use in humans. Subsequent innovations led to the creation of human papillomavirus (HPV) vaccines, which are also based on recombinant protein technology. With the advent of the COVID-19 pandemic, rapid progress was made in the development of subunit vaccines against SARS-CoV-2. Laboratories and pharmaceutical companies quickly adapted their recombinant protein production platforms to produce vaccines such as the Recombinant Coronavirus Spike Protein Antigen by Shionogi and the HIPRA SARS-CoV-2 vaccine. Other milestones include the development of the recombinant vaccines by companies like Recbio Technology, WestVac Biopharma, Sichuan Clover Biopharmaceuticals, and Novavax. Over time, improvements in recombinant expression, formulation with innovative adjuvants (like Matrix M), and advancements in delivery systems have shaped the evolution of subunit vaccines into safe and effective products ready for emergency and routine use.

Types of Drugs Associated with Subunit Vaccines

Within the realm of genetically engineered subunit vaccines, different drug types and therapeutic formulations are available. These drugs are primarily classified based on their antigen source, production platform, and intended prophylactic or therapeutic use. The current landscape, largely driven by the global need for COVID-19 immunization, now includes multiple recombinant subunit vaccine formulations based on the SARS-CoV-2 spike protein and its variants.

Classification of Drugs

Genetically engineered subunit vaccine drugs can be broadly classified as follows:

- Prophylactic Vaccines: These are vaccines that are administered to healthy individuals to prevent disease. They are designed to trigger an immune response before exposure to the pathogen. Most genetically engineered subunit vaccines, such as those for COVID-19, operate in this prophylactic mode.

- Genetically Engineered Protein-Based Vaccines: This category includes drugs produced via recombinant expression techniques. The vaccine components are high-purity proteins (or fragments thereof) that are expressed in cell culture systems such as mammalian cells, yeast, or insect cells. They are engineered to mimic the key structural elements of the pathogen’s surface proteins (for instance, the S protein or RBD of SARS-CoV-2).

- Virus-Like Particle (VLP) Vaccines: Although not exclusively subunit vaccines, VLPs share features with genetically engineered subunit vaccines. They are self-assembled structures composed of viral proteins that mimic the virus’s native conformation without containing any viral genetic material. This approach provides enhanced immunogenicity while maintaining safety. However, most of the drugs discussed in the genetic engineering category are produced as single recombinant proteins or trimers that mimic the native S protein.

- Multivalent Vaccines: Some subunit vaccines are designed to be multivalent, hence including more than one antigenic component. An example is the Human Papillomavirus (HPV) vaccine which may incorporate antigens from several HPV types. Despite the fact that HPV vaccines focus on neoplasms and urogenital diseases, the principle of utilizing multiple antigenic epitopes to enhance immunogenicity is directly relevant to genetically engineered subunit vaccines.

- Combination Vaccines: In certain cases, subunit vaccines are combined with adjuvants and other immune stimulants to create a formulation that not only presents the antigen but also actively engages the innate immune system. Adjuvants such as Matrix M, aluminum salts, and novel toll-like receptor agonists are combined with the recombinant protein to improve its immunogenic profile. This combination is a hallmark of many genetically engineered subunit vaccines developed against COVID-19 and other pathogens.

Examples of Specific Drugs

A range of specific drugs based on the genetically engineered subunit vaccine approach is available. Some notable examples include:

- Recombinant Coronavirus (SARSCoV-2) Spike Protein Antigen (Shionogi): This vaccine, developed by Shionogi & Co., is a prophylactic vaccine that uses the full-length recombinant spike protein. It is designed to inhibit the interaction of the virus with host cell receptors and has been approved for use in Japan as of June 2024.

- HIPRA SARS-CoV-2 Vaccine (Laboratorios HIPRA): Using a genetically engineered subunit platform, this vaccine also targets the SARS-CoV-2 spike protein—its mechanism involves modulating the spike antigen to induce a robust immune response. It is widely approved in the European Union and neighboring regions.

- Recombinant Covid-19 Vaccine (Recbio) (Jiangsu Recbio Technology Co., Ltd.): This vaccine employs a recombinant spike protein produced using advanced genetic engineering methods. It was first approved in Mongolia, targeting the SARS-CoV-2 S protein with a mechanism that introduces spike protein modulators, thereby ensuring effective prophylaxis.

- Recombinant Protein COVID-19 Vaccine (WestVac Biopharma): Developed by West China Hospital in collaboration with Chengdu Weisk Biopharmaceutical Co., Ltd., this vaccine uses a recombinant protein approach to present the key viral antigen, and its mode of action includes spike protein inhibition to achieve an immunostimulatory effect.

- COVID-19 S-Trimer Vaccine (Sichuan Clover Biopharmaceuticals, Inc.): This formulation leverages a trimeric structure of the spike protein to better mimic the native configuration found on the virus. It effectively induces immune responses through both spike protein modulatory and immunostimulant activities.

- Subunit Recombinant Vaccine (St. Petersburg Research Institute of Vaccines and Sera): This vaccine, also based on a recombinant subunit approach, is designed to stimulate strong immuno-modulatory responses following its administration. It is administered as a prophylactic vaccine aimed at COVID-19 prevention.

- SARS-CoV-2 Spike Protein Vaccine by Novavax (Novavax, Inc.): One of the most prominent examples globally, this vaccine uses a recombinant spike protein nanoparticle formulation combined with the Matrix-M adjuvant. Its recombinant subunit vaccine technology has demonstrated high efficacy rates in phase III clinical trials.

- MVC-COV1901: Developed by the National Institutes of Health, this vaccine is another genetically engineered subunit formulation, primarily produced as a recombinant protein that is stabilized for enhanced immunogenicity. It has been approved for use in Taiwan and targets the SARS-CoV-2 spike protein.

- Recombinant SARS-CoV-2 Vaccine (CHO Cell) (Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.): This vaccine relies on the CHO cell expression system to produce the SARS-CoV-2 spike protein and is formulated as a recombinant subunit vaccine. It has been approved in Uzbekistan and emphasizes the use of spike protein inhibitors.

- Human Papillomavirus (HPV) Vaccine (Recombinant bivalent vaccine by Walvax Biotechnology Co., Ltd. and Shanghai Zerun Biotechnology Co., Ltd.): Although not targeted at infectious respiratory diseases, this vaccine is a quintessential example of a recombinant protein-based subunit vaccine used to prevent HPV-associated cervical carcinoma. It combines virus-like particle technology with an emphasis on immunostimulants.

Collectively, these examples illustrate the diversity within genetically engineered subunit vaccine drugs. They vary by the choice of expression system, the structure of the antigen (full-length protein, trimeric forms, or fragments like the receptor binding domain), and the selection of adjuvants used to enhance the immune response. This diversity allows for targeted immunoprophylaxis across different pathogens and patient populations, ensuring a high degree of specificity and safety.

Development and Application of Subunit Vaccine Drugs

The development pathway of genetically engineered subunit vaccine drugs is a complex, multi-step process that spans from initial antigen discovery to regulatory approval and clinical application. The engineering and production of these vaccine drugs benefit from modern biopharmaceutical techniques and detailed quality control processes that ensure both potency and safety.

Drug Development Process

The development of subunit vaccine drugs typically follows these stages:

- Antigen Identification and Selection:
The process begins with the identification of a targeted antigen, such as the S protein in SARS-CoV-2 vaccines, chosen for its role in viral entry and its capacity to elicit a neutralizing immune response. Advances in bioinformatics and structural biology have greatly enhanced the initial selection by enabling screening for immunodominant epitopes.

- Recombinant Expression:
Once the antigen is selected, the gene encoding the antigen is cloned and inserted into an appropriate expression vector. This vector is then introduced into a host cell line (bacterial, yeast, insect, or mammalian systems) that has been optimized for high-yield expression of the protein. The choice of expression system has significant implications for post-translational modifications, protein folding, and ultimately immunogenicity.

- Purification and Quality Control:
The protein is purified using chromatographic methods to ensure high purity. Quality control measures, such as protein characterization by mass spectrometry and structural analysis, are essential to confirm that the antigen retains the proper conformation necessary for inducing the desired immune response. These procedures are crucial to meet current Good Manufacturing Practice (cGMP) standards.

- Formulation with Adjuvants:
Given that subunit vaccines are inherently less immunogenic due to the absence of pathogen-associated molecular patterns (PAMPs), an adjuvant is added during formulation. Adjuvants not only enhance the immune response but also may modulate it toward a Th1 or Th2 profile, depending on the target pathogen. Examples include aluminum salts, saponin-based Matrix M, and toll-like receptor agonists, which have been successfully combined with recombinant proteins.

- Preclinical and Clinical Evaluation:
Before clinical trials, the formulated vaccine undergoes extensive preclinical testing in animal models to assess immunogenicity and safety. Once preclinical data are deemed acceptable, the vaccine progresses through Phase I (safety and dosage), Phase II (proof-of-concept and immunogenicity), and Phase III (large-scale efficacy and safety) trials. This rigorous process ensures that the final product can be approved by regulatory bodies such as the FDA and EMA.

- Manufacturing and Distribution:
The manufacturing process for genetically engineered subunit vaccine drugs is highly scalable, leveraging bioreactor technology for mass production. Challenges such as ensuring uniform potency and cold-chain logistics are managed via standardized, automated production platforms.

Clinical Applications and Use Cases

Genetically engineered subunit vaccine drugs have primarily been applied in the prophylactic setting for infectious diseases. The following are key applications:

- COVID-19 Prophylaxis:
The COVID-19 pandemic led to the rapid development and global deployment of several recombinant subunit vaccines. Drugs such as those from Shionogi, HIPRA, RecBio, WestVac Biopharma, and Novavax have undergone extensive clinical testing and have been authorized for emergency or regular use. Their design is tailored to produce a robust neutralizing antibody response against the SARS-CoV-2 spike protein and is often enhanced by a suitable adjuvant formulation.

- Prevention of HPV-Related Diseases:
Beyond COVID-19, the recombinant HPV vaccine (e.g., by Walvax Biotechnology and Shanghai Zerun Biotechnology) illustrates the application of subunit vaccines in preventing virus-induced cancers such as cervical carcinoma. These vaccines work by inducing protective antibodies that neutralize HPV, thereby preventing persistent infections and subsequent neoplastic transformations.

- Potential for Future Applications:
The technology underlying genetically engineered subunit vaccines holds promise for rapidly addressing emerging infectious diseases, such as future coronavirus or influenza pandemics. The modularity of recombinant vaccine platforms allows for rapid redesign and inclusion of antigens from new variants, thereby ensuring adaptability in the face of viral evolution.

Efficacy and Safety Considerations

Evaluating the efficacy and safety profiles of genetically engineered subunit vaccines is critical, given that these factors directly impact public health outcomes, vaccine acceptance, and long-term protection.

Efficacy Studies and Data

The efficacy data for genetically engineered subunit vaccines have reached impressive levels in many clinical trials:

- Clinical Trial Outcomes:
For instance, Novavax’s recombinant spike protein vaccine has demonstrated efficacy rates exceeding 90% in phase III clinical trials, thereby underscoring the potential of recombinant subunit technology in providing high-level protection against COVID-19. Similarly, other subunit vaccines like HIPRA SARS-CoV-2 and RecBio’s vaccine have reported robust neutralizing antibody titers, translating to high protection rates in diverse populations.

- Immune Response Characteristics:
The immune responses elicited by these vaccines are typically characterized by a Th1-biased profile, marked by high levels of interferon-gamma (IFN-γ) production by T cells, as well as potent neutralizing antibody responses against the S protein. This balanced response minimizes the risk of adverse events, such as vaccine-associated enhanced respiratory disease (VAERD), while ensuring prolonged immunity. Moreover, certain formulations, such as the COVID-19 S-Trimer vaccine, leverage the multimeric presentation of antigens to mimic the native viral structure, leading to a more robust activation of B cells.

- Correlates of Protection:
A significant amount of research has focused on identifying immune correlates of protection that are specific to recombinant subunit vaccines. Parameters such as neutralizing antibody titers, T-cell responses, and the longevity of immune memory have been used to gauge efficacy. These correlates are continually refined through preclinical studies and Phase IV (post-marketing) surveillance.

Safety Profiles and Side Effects

One of the most attractive aspects of genetically engineered subunit vaccine drugs is their favorable safety profile:

- Intrinsic Safety:
Owing to their purified composition, these vaccines do not contain live pathogens or potentially harmful viral components. This intrinsic safety significantly reduces the risks of reversion to pathogenic forms—a concern that has been observed with live-attenuated vaccines. Subunit vaccines also circumvent the complexities related to whole-virus inactivation processes, which sometimes lead to residual toxic substances.

- Adverse Events:
Clinical trials involving recombinant subunit vaccines have consistently shown that these formulations are associated with mild to moderate adverse effects. Common side effects include local reactions at the injection site (pain, redness, swelling) and transient systemic symptoms such as fever or fatigue. Serious adverse events have been rare and generally not attributable to the vaccine component itself but rather to individual host factors. The side effect profile is often improved when appropriate adjuvants are carefully selected. For example, adjuvants such as Matrix-M and aluminum salts have been optimized to enhance immunogenicity while maintaining a low incidence of adverse events.

- Booster and Multi-dose Regimens:
Due to the inherently lower immunogenicity of purified protein components, genetically engineered subunit vaccines may require booster doses. Although multi-dose regimens might increase the cumulative mild adverse events, the benefit of sustained immunity and improved protection outweighs these transient effects. Continuous safety monitoring is an integral part of post-marketing surveillance to identify any long-term or rare adverse effects.

Future Trends and Research Directions

The field of genetically engineered subunit vaccine drugs is rapidly evolving. Building on decades of experience with recombinant protein technology, future developments are set to further enhance vaccine performance, broaden applicability, and address emerging challenges in immunization strategies.

Innovations in Subunit Vaccine Drugs

Several innovative trends are currently shaping the future landscape:

- Next-Generation Antigen Engineering:
Advances in structural vaccinology and protein engineering are paving the way for the design of antigens that more closely mimic the native conformation of the pathogen. This can boost immunogenicity and prolong the durability of the immune response. For instance, designing stabilized prefusion conformations of the spike protein has already yielded promising outcomes in clinical trials. Gene editing and computational modeling are increasingly integrated into antigen design, allowing for rapid adaptation in response to emerging variants.

- Novel Adjuvant Systems and Delivery Platforms:
The combination of recombinant antigens with cutting-edge adjuvants is critical to compensating for the inherent immunogenicity limitations of subunit vaccines. Research is moving toward the use of nanoparticle-based delivery systems that not only act as carriers but also exert intrinsic adjuvant effects. These include self-assembling protein nanoparticles, lipid nanoparticles for mRNA stabilization, and advanced formulations that enhance lymph node targeting. Integrating nano-adjuvants with recombinant proteins can ensure more efficient antigen presentation and safer profiles.

- Broad-Spectrum and Multi-Epitope Vaccines:
Technological progress has enabled the design of multivalent vaccines that target multiple epitopes or even multiple pathogens simultaneously. This is particularly relevant for diseases where antigenic drift is a challenge. For instance, combining multiple conserved regions from the SARS-CoV-2 spike protein could help produce a vaccine that maintains efficacy despite viral evolution. Similar approaches are being explored for the next generation of influenza and other respiratory vaccines.

- Personalized Vaccinology:
Advances in genomics and the identification of immune biomarkers will eventually allow for personalized vaccination strategies. By tailoring vaccine compositions and dosing regimens to individual genetic backgrounds or immune profiles, the risk of vaccine failure or adverse events could be minimized. Biomarker-driven approaches may also contribute to streamlined regulatory pathways and more efficient vaccine delivery in the future.

Emerging Challenges and Opportunities

Despite the remarkable progress, several challenges remain that will shape future research and development in genetically engineered subunit vaccine drugs:

- Manufacturing Scale-Up and Global Distribution:
As demonstrated by the rapid global deployment of COVID-19 vaccines, manufacturing capacity is a critical factor. Although recombinant protein production is highly scalable, ensuring consistent quality in large batches and addressing cold-chain logistics, especially in lower-resourced regions, are ongoing challenges. Innovations in production technologies such as continuous manufacturing and modular bioprocessing systems are being explored to overcome these hurdles.

- Adaptive Regulatory Frameworks:
The unprecedented speed of vaccine development during emergencies has necessitated regulatory flexibility. As genetically engineered subunit vaccines become more prevalent, regulators must continuously adapt to new technological paradigms while maintaining stringent safety and efficacy standards. Ongoing discussions about adaptive clinical trial designs and accelerated approval processes will be crucial to enable rapid responses to emerging diseases without compromising public safety.

- Vaccine Hesitancy and Public Communication:
Even with strong efficacy and safety data, public acceptance can be a significant barrier. Transparent communication regarding the rationale for using recombinant proteins, the safety measures in place, and the benefits of multi-dose regimens is essential. As these vaccines continue to play a pivotal role in public health, efforts must be made to educate and engage communities, particularly those with historically higher levels of vaccine hesitancy.

- Long-Term Immunity and Boosting Strategies:
While short-term efficacy data for many genetically engineered subunit vaccines are promising, ensuring long-term immunity remains a challenge. Research efforts are focused on understanding the durability of immune memory induced by these vaccines, which may ultimately influence booster dosing strategies. Innovations such as self-boosting nanoparticle formulations and engineered adjuvants that promote sustained antigen release are areas of active investigation.

- Emerging Pathogens and Pandemic Preparedness:
The rapid response to COVID-19 has underscored the importance of having flexible vaccine platforms ready for use against emerging pathogens. Genetically engineered subunit vaccines, with their modular design and relatively short development cycles, are well-suited for this role. Future research will likely invest in “prototype” vaccine candidates for virus families with pandemic potential, using recombinant strategies that can be quickly adapted when a novel strain emerges.

Conclusion

In summary, genetically engineered subunit vaccines represent a highly promising class of drugs that combine precision antigen design with modern biomanufacturing techniques to achieve effective and safe prophylaxis against infectious diseases. The development of these drugs leverages recombinant protein technology to present critical antigens—predominately the spike protein in the case of COVID-19—in a purified form that minimizes adverse reactions compared to traditional vaccines. Current examples include the Recombinant Coronavirus Spike Protein Antigen by Shionogi, the HIPRA SARS-CoV-2 vaccine, the RecBio vaccine, WestVac Biopharma’s formulation, the COVID-19 S-Trimer vaccine, the Novavax spike protein vaccine, MVC-COV1901, and the CHO cell-based recombinant vaccine from Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. Additionally, other recombinant-based vaccines, such as those for human papillomavirus, illustrate the breadth of the technology.

The development and application of these drugs follow a rigorous path—from antigen identification and recombinant expression to advanced formulation with adjuvants and comprehensive clinical evaluation—which ensures that these vaccines not only confer high levels of protection but also maintain excellent safety profiles. Efficacy studies have demonstrated that these vaccines induce robust immune responses, often characterized by a Th1-skewed profile and high neutralizing antibody titers. Safety data have also been very encouraging, with adverse events typically limited to transient, mild-to-moderate local and systemic reactions.

Looking forward, the future of genetically engineered subunit vaccine drugs lies in continued innovation in antigen design, adjuvant systems, and delivery platforms. Challenges such as manufacturing scale-up, adaptive regulatory frameworks, public communication, and long-term immunity need to be addressed. Nonetheless, the flexibility and rapid adaptability of recombinant subunit technologies offer significant opportunities for pandemic preparedness and personalized vaccinology.

In conclusion, genetically engineered subunit vaccines provide an excellent balance of safety, efficacy, and adaptability. Their development has transformed preventive medicine, allowing for fast-tracked responses to emerging pathogens and the ongoing improvement of vaccine design. As research continues to refine antigen stability, adjuvant integration, and manufacturing efficiency, subunit vaccine drugs are set to play an increasingly critical role in global public health, offering innovative solutions to both current and future infectious disease challenges.