Prophylactic and therapeutic vaccine development: advancements and challenges

Introduction

Biomedical science encompasses fields such as biology, chemistry, physics, and engineering. It enhances our understanding of diseases, formulates remedies, and prevents pandemics [1]. A pandemic is an epidemic affecting large areas, multiple countries, or the entire world, causing more havoc than smaller, seasonal outbreaks. They tend to cause more havoc than smaller seasonal outbreaks or epidemics [2]. There is a strong association between using biomedical science to interpret the pandemics. Biomedical science is critical in interpreting pandemics by studying pathogens and their effects and developing diagnostic tools. For example, during the COVID-19 pandemic, biomedical scientists researched virus transmission, provided health guidelines, and developed surveillance techniques to curb the outbreak. This underscores the importance of integrating biomedical science into medical education. It also helps study the pandemic, the pathogen, and its effects [3]. One of the new budding applications in biomedical science to put a stop to the pandemic is diagnostic tool development. A recent case can be seen with the example of COVID-19 [4, 5]. Biomedical scientists have put their time into researching the transmission of the viruses. This gives valuable knowledge to develop health-related guidelines for the public to curb the virus's transmission and halt the outbreak. Researchers have also focused on looking into ways to detect the transmission of the virus. This involves various surveillance techniques that again help stop the outbreak before it gets widespread [6]. The rapid development of COVID-19 vaccines, particularly the mRNA-based vaccines, highlights the potential to apply similar strategies to other serious diseases. However, market uncertainty and lack of awareness can complicate the vaccine development. Understanding vaccination, introducing non-active disease-causing organisms, and the historical advancements in vaccine development are crucial for future progress [7].

The vaccine development process for COVID-19 showed the speed of development and has led us to focus on similar strategies for other serious diseases [8–10]. The path to vaccine development can be simple or highly complex. However, the factors that may complicate the entire process are market uncertainty or lack of awareness of the path for vaccine development [11]. As to what vaccination is, it is the provision of a non-active disease-causing organism to the living body. Vaccination, especially the one with the traditional development process, did not garner much attention in comparison with the vaccines developed by newer mRNA-based technology [10]. Vaccination helps in the induction of the antibodies and the T cell response. This helps keep the person safe against a variety of disease-causing organisms. These vaccines can be prophylactic or therapeutic. Prophylactic vaccines are preventive, while therapeutic vaccines are used post-infection [12].

Experience and observation to practice 'variolation' were used by people in the twelfth and fifteenth centuries [13], and the practice of variolation was the first known form of immunization of humans. Fluid or powdered scabs from the blisters of a smallpox patient were transferred into the recipient's skin via minor scratches on the surface. This technique was employed in diverse formats across China, the Middle East, and Africa before it was eventually transmitted to Europe in the seventeenth century. Edward Jenner inaugurated the seminal scientific investigation in 1796, using smallpox scabs and viruses from cowpox instead of mystery materials and performing human experiments based on Enlightenment principles. The vaccination process also got its name from Jenner; this marks the dawn of vaccinology [14]. Creating a vaccine usually involves a decade to fifteen years of research conducted predominantly within commercial entities' laboratories, often necessitating collaborations with university-based researchers.

The concept of vaccination came up in Europe in the eighteenth and nineteenth centuries, and significant advancements were made in the twentieth century due to developments in molecular biology and biotechnology [5]. Computational technology has also added to the development of vaccines. Programs and algorithms (Vaxign, Bowman-Heinson, VacSol, NERVE) are built around bacterial and prokaryotic systems that aid the process [15]. The ultimate aim is to target diseases like the Human Immunodeficiency Virus, Ebola, Zika virus, severe acute respiratory syndrome, dengue, chikungunya, and all cancer types: hepatitis and tuberculosis. However, on the downside, this has thrown light on the need for growth in the vaccine development market in the past 40 years [12, 16].

This review highlights the development of prophylactic and therapeutic vaccine processes with advancements and challenges. This article aims to provide a comprehensive overview of the latest advancements and challenges in developing prophylactic and therapeutic vaccines. It explores innovative vaccine technologies, such as mRNA and viral vectors, while addressing critical scientific, regulatory, and societal challenges. The article also highlights the ethical considerations and public perception issues that impact vaccine development and deployment, emphasizing the critical role of vaccines in modern medicine and public health.

Fundamental concepts of prophylactic and therapeutic vaccine

Immunity is the body's ability to protect itself and withstand against damaging foreign bodies. It can be innate immunity or acquired immunity. The underlying principles of preventive and therapeutic vaccinations stem from the body's immune response, which can be classified into innate immunity and adaptive immunity. Innate immunity is the body's first shield against foreign constituents. It has a similar response to germs and foreign bodies. It is also called as "non-specific" immunity [17]. It is not because of a vaccine or an infection. This can be via physical barriers or internal defenses, namely skin, hair, cilia, mucus membranes, stomach acid, digestive enzymes in the mouth, and so on [18]. In the case of vaccinations, this initial reaction is crucial because it aids in stimulating the immune system as a whole, laying the groundwork for the longer-lasting and more focused adaptive immune response. For vaccines to effectively mount a defense against infections or diseases, they must activate the immune system during this early stage, both preventive and therapeutic [19].

The adaptive immune system is the system that provides a specific type of immunity and is based on memory. Typical features include specificity, heterogeneity, and memory [20]. The success of vaccinations is primarily dependent on the adaptive immune system, which provides long-term protection and is very specialized. The two primary components of a focused immune response that the body mounts in response to a pathogen or vaccine antigen are B cells, which generate antibodies, and T cells, which either directly attack diseased or infected cells or work together to coordinate the immune response. T cells are made in the bone marrow and use chemical messengers to activate other immune system cells. B cells are made in bone marrow but are activated by T cells. They turn into memory cells and help with the memory component of adaptive immunity [17].

Establishing immunological memory is a critical component of adaptive immunity, enabling the immune system to react to disease more quickly and efficiently the next time. This idea is essential to the goal of preventive vaccinations, designed to create memory B and T cells that remain in the body to create long-lasting protection. This is a function of specificity and longevity [21]. The Greeks first recorded this, and it has now become a vaccine. The memory is maintained by long-lived antigen-specific lymphocytes brought in by the first exposure and continues until a second interaction with the pathogen. This memory can be measured as adoptive transfer assays of lymphocytes. The entire process comprises an initial response by a primary antibody and then a secondary antibody, which comes in later. The production of IgM, IgG, IgA, and IgE marks the secondary antibody response. A secondary immune response will come into play upon a second interaction with the same antigen [22].

These memory cells can quickly create a defense to stop the sickness from spreading when they come into contact with the same infection again. Though they frequently aim to elicit a more rapid and robust immune response, mainly when the disease is already established, like in chronic infections or cancer, therapeutic vaccines also use immunological memory. Depending on the vaccination's intended use, the ultimate objective in each scenario is to teach the immune system how to react to particular antigens more successfully, either for preventive or therapeutic purposes. A thorough understanding of the molecular mechanisms behind immune activation and the biological mechanisms of infections is crucial for creating preventive and therapeutic vaccines. The development of vaccines depends on figuring out the distinct features of pathogens, like viruses or bacteria, that can be attacked to trigger a potent and successful immune response. Scholars in virology, pathogen biology, and molecular biology can identify particular antigens that elicit the immune system to identify, combat, and retain the infection. This knowledge helps develop therapeutic vaccinations that strengthen the immune system's capacity to combat pre-existing illnesses, including cancer and chronic infections, and vaccines that prevent infection [17].

Virology refers to the study of viruses and infections caused by them. They can infect all life forms (bacteria, plants, protozoa, fungi, insects, fish, reptiles, birds, and mammals). They are small, subcellular agents that cannot multiply out of a host cell. Thus, they are intracellular and obligate parasites. They can either have a viral Deoxyribonucleic Acid (DNA) or Ribonucleic Acid (RNA) and cause a variety of diseases like HIV (Human Immunodeficiency Virus), ebola, herpes, chicken pox and so on [23]. Pathogens, unlike general thinking, are not limited to hostility. It lives at the expense of the host [24]. In scientific terms, it is defined as an organism causing disease to its host, with the severity of the disease symptoms referred to as virulence [25]. They can be facultative or obligate. Obligate pathogens need a host to complete their life cycle; this can be one host or multiple. Facultative pathogens are mainly environmental bacteria or fungi, requiring a host only as a niche. Furthermore, knowing a pathogen's virulence, or the degree of the disease it causes, aids in developing vaccinations that either weaken the pathogen or expose the immune system to a safe form of its antigen [26].

Molecular biology is an essential field in vaccine development that studies the interactions between proteins, RNA, and DNA [27]. Nucleic acids are simpler than proteins since they comprise only four main types of bases joined via a chain of sugars and phosphates. The sequence of these bases in the DNA of any organism forms its genetic information. This sequence makes all of the proteins an organism can produce, all of the chemical reactions it can carry out, and all of the behavior the organism can showcase as an answer to its environment [28]. Researchers have also quickly found new antigens and enhanced vaccine formulation because of developments in molecular biology, such as genome sequencing [29].

Vaccines, whether preventive or curative, utilize the body's natural defenses against infections and illnesses, both innate and adaptive. The body's first line of defense is the innate immune response, while memory cells produced by the adaptive immune system give the body specialized, long-lasting protection [30]. Whether creating vaccines to prevent infections or cure pre-existing diseases like cancer and chronic infections, a thorough grasp of virology, pathogen biology, and molecular pathways is crucial. By making it possible to identify antigens and improve vaccine composition precisely, recent developments in molecular biology have sped up the research on vaccinations and held out hope for the day when vaccines may be customized for both therapeutic and preventive uses [31].

Vaccine development process

Vaccines serve an essential role in world health. They contribute to longer, healthier lives and higher quality of life. Vaccination is an effective means to avoid several dangerous and contagious diseases. It has been identified as one of the most essential approaches to combat a pandemic [32]. Its applications include smallpox and polio eradication [33]. Vaccination has substantially decreased the prevalence of many pediatric illnesses, including measles and polio [34]. Influenza vaccination is routinely used yearly to guarantee influenza prevention during the season [35]. As a result, many scientific studies have recognized vaccination as one of the most efficacious disease transmission prevention measures through stopping disease transmission. Infectious diseases as human health problems are one of the biggest concerns in healthcare [36]. Terrifying are the diseases that spread around, especially those that kill many victims. Traditionally, viral infections were considered among the misfortunes or the expressions of a deity's wrath from the earliest times of humanity [37].

Advancements in the etiological study of diseases caused by viruses, knowledge of microbiology, and the discovery of different vaccines have prevented humanity from its unreasonable fear of death. The invention of vaccines and their development is regarded as one of the most outstanding achievements in medical history. Millions of lives have been saved because of vaccination, and its value is only expanding. Despite extensive efforts that have been made to develop competent and productive vaccines, there are inadequate obstacles to protecting people from diseases that could produce outbreaks or widespread diseases affecting a large number of people [38, 39]. Therefore, researchers are attempting to extend the number of illnesses that vaccinations can stop, thereby broadening the target populations who will benefit from vaccination in the future. Moreover, the techniques of developing vaccines are customized to meet individual countries' distinct wellness and financial needs. Before introducing a vaccine to the community, some initial stages should be gone through, such as proof of concept, vaccine testing, and the final vaccine manufacturing process.

Therapeutic vaccine development process

Immunotherapy through therapeutic vaccines is a viable and efficient approach for tackling new illnesses, chronic diseases, and existing epidemic and endemic diseases. They have safety, precision, in and out, and tumor enlargement can respond, so it is most effective. However, most therapeutic vaccines are still being tested in clinical trials to ensure they offer effective results. Nevertheless, better comprehension of the flow of immune reactions associated with the vaccines and burning immunomodulatory approaches could enhance the clinical applicability and efficacy of the vaccines [61]. Efforts to progress therapeutic vaccines should focus on three key areas: choosing an antigen, testing for an antigen, and deciding on the delivery method of antigens therapeutically or otherwise, which come in handy. It is also important to point out that searching for stable antigens associated with differing pathophysiologic events often requires a better understanding of pathophysiologic processes. For example, a better understanding of tumor-associated antigens, neoantigens, and natural immune responses has improved vaccine design in tumor immunology [62]. Regarding optimal results, the quality of neoepitopes should be improved more.

Antigen delivery is heavily influenced by the adjuvant used and the route of administration. Each form of therapeutic vaccination has distinct advantages and disadvantages. Protein/peptide vaccines are easy to produce but have limited immunogenicity. Vector-based vaccinations often deliver antigens with excellent effectiveness but raise safety issues. DNA vaccines lack a robust immunological response [63]. Activating adjuvants can boost the innate immune system's cellular and molecular components, thereby augmenting the efficacy of protein/peptide and DNA vaccines.

Moreover, emerging carrier systems such as lipoplex, liposomes, and self-assembling nanoparticles are anticipated to significantly contribute to developing protein/peptide vaccine platforms. Further, installing other/novel therapies like immune checkpoint inhibitors, CAR-T cell therapy, and TCR-T therapy shall also improve therapeutic vaccines. It has been found that therapeutic interfaces are enhanced when neoantigen vaccines are administered in combination with other immunotherapies. This is because, in chronic viral infections, the virus-specific T cells are gagged, letting them be exhausted quickly [64]. In vivo, inhibition of the PD-1/PD-L1 pathway positively impacted the efficacy of the therapeutic HBV (Hepatitis B virus) vaccine in the LCMV mouse model [65].

Chronic non-communicable diseases are a leading contributor to illness and death on a global scale, responsible for 71% of all fatalities and exerting a considerable impact on the global economic burden [66]. Chronic non-communicable diseases encompass conditions such as cardiovascular disease, cancer, respiratory illnesses, diabetes, hypertension, Alzheimer's disease, dyslipidemia, asthma, and chronic obstructive pulmonary disease [67]. Over 80% of fatalities stem from the leading quartet of chronic non-communicable illnesses, comprising cardiovascular diseases, cancer, respiratory ailments, and diabetes [6]. Thus, therapeutic vaccine development is desirable for an established disease that can go around the body's immune system to achieve a targeted immune response and constant destruction of the known disease. These vaccines provoke antigen-specific immune responses to prevent infected cells from escaping elimination [68]. In 1890, Koch developed the therapeutic vaccine for Tuberculosis (TB) known as Tuberculin, which consists of Tuberculin suspended in glycerol to create a preparation. This marked a significant advancement in distinguishing vaccines' preventive and healing capabilities [69]. Following Almroth Wright's depiction of employing a comparable antibacterial immunization for addressing prolonged regional bacterial infections in 1897, therapeutic vaccines underwent swift advancement yet simultaneously provoked considerable controversy due to misuse [70].

The different compounds and antibiotics have affected the researchers' challenge of therapeutic vaccines. Since HIV was first discovered in early 1981, antiviral immunology has been rapidly advancing. Healthcare reforms, changes in disease nature and patterns, particularly of chronic diseases, and the growing prevalence of antibiotic-resistant bacteria have influenced therapeutic vaccine development again intensively after the approval of Sipuleucel-T in 2010 [71], The development of therapeutic vaccines gained momentum, with numerous studies demonstrating their beneficial clinical role in treating tumors and infectious diseases [72]. Based on fundamental research, they have begun moving towards the stage of clinical trials, and this reflects the scholarly literature foundations. Currently, many therapeutic vaccines are under clinical trials for therapeutic uses in both communicable and non-communicable illnesses, infective and non-infective, such as viral diseases, cancer, hypertension, Alzheimer's disease, diabetes, and dyslipidemia [73]. Therapeutic vaccinations offer numerous advantages compared to contemporary chemical or biological treatments. These include precise targeting, minimal adverse effects, enduring efficacy, and immunity to drug resistance. They present a promising avenue for combating infectious diseases and chronic non-communicable conditions, offering renewed optimism for treatment [74]. Figure 2 shows the precision vaccinology approach.

Vaccine development technologies and innovations

Many advanced technologies and advances have revolutionized the vaccine development landscape. These developments cover various approaches, such as CRISPR-cas systems, protein subunit vaccines, nanoparticle vaccines, viral vector vaccines, and nucleic acid vaccine technology. Every strategy offers distinct benefits and innovations that improve vaccine development processes' safety, effectiveness, and speed (Fig. 4). In this section, authors have discussed selective technologies.

Key challenges in vaccine development and deployment

Developing effective vaccines involves overcoming numerous challenges. This highlights a few challenges, including delivery methods, antigen identification, and transportation and storage logistics. These challenges are critical to ensuring the success of vaccination campaigns and improving public health outcomes.

Ethical and regulatory considerations in vaccine development

During vaccine development, distribution, and implementation of vaccinations, the four bioethics principles should be considered: justice, non-maleficence, autonomy, and beneficence. There are usually some challenges during the implementation of the ethics [233]. Distributive justice, rights-based justice, and legal justice are the three components of a fair decision that make up justice. Distributive justice refers to the equitable allocation of limited resources to all; equality denotes the lack of avoidable or compensable differences between various groups, nations, racial and ethnic groups, and societies at large [234].

Concerning the justice principle, the limited supply of COVID-19 vaccines that have been licensed, the strong demand from many nations, and nationalism, it may be extremely difficult or even impossible to distribute vaccines equitably [235]. According to the Adejumo et al. study, concerns like the differences in the economic standing of the nation's signing contracts with vaccine manufacturers and the lack of logistical support should not stand in the way of guaranteeing universal access to vaccines in line with the sustainable development goals—concerns like the elderly and healthcare workers being prioritized [236].

Vaccine makers must consider inclusion and exclusion criteria, such as laboratory and clinical evaluations when conducting clinical trials to include healthy people in the study [237]. As soon as the sponsors and health department inspectors verify safety and temporary efficacy, participants receiving a placebo in a clinical trial should have the right to obtain the vaccine, which should be guaranteed and safeguarded. This right should also be mentioned in the informed consent forms [238].

The existence of a comprehensive treatment facility is another problem, as it guarantees trial participants access to care and treatment in the event of any significant adverse events connected to the results of clinical trials [239]. The right to autonomy in healthcare refers to the patient's ability to make decisions about their treatment plans based on their values, attitudes, and assessments [240]. Furthermore, To "not harm" the essential and foundational tenets of medical care and research is to adhere to non-maleficence, sometimes known as "not to harm" [241].The Advisory Committee states that while allocating the COVID-19 vaccine, consideration should be given to four principles: maximizing benefits and reducing harm, promoting fairness, alleviating health inequities, and encouraging transparency [242].

The principles of beneficence and non-maleficence must be approached holistically by the notion of beneficence. Public gains thus outweigh public harms. Thus, the beneficence concept merits special consideration in clinical trials and immunization programs. In order to do this, researchers should ensure that the cumulative benefits of public health interventions surpass the drawbacks and play a significant role in containing and preventing the COVID-19 outbreak, both during the vaccine development and immunization stages [243].

Furthermore, the concept of beneficence may impact the principle of autonomy in the event of a national pandemic threat. In order to vaccinate children and adolescents, accurate information regarding the immunogenicity of vaccines should be available [233]. The public's willingness to accept the vaccine may be impacted by a lack of faith in the vaccine's efficacy and safety resulting from mistrust of scientific research, a lack of proof and information, exposure to false information about the vaccine, fear of politicization, and pharmaceutical industry misuse of the vaccine [244]. Consequently, a reliable information system must be in place for the community to make an informed decision regarding vaccinations [245].

Conclusion and future prospects

Finding vaccination platforms capable of achieving high immunogenicity is essential, even if therapeutic cancer vaccines represent an intriguing new frontier to overcome the long-standing cancer treatment conundrum [246]. Furthermore, individual differences in tumor antigens must be addressed for an improved anti-tumor response. In order to improve clinical results, future research should concentrate on refining vaccination platforms and optimizing combination therapy to increase immunogenicity [247]. Delivering cargo with predetermined release kinetics and duration of impact to a target location or site is the goal of a drug/vaccine delivery system. As vaccination research becomes more specialized and focused, we must constantly create new delivery methods to keep up with the times. While targeting and efficiency in delivery systems are essential, the safety and practicality of clinical translation of the delivery system itself should receive greater emphasis [248].

Prospective progress toward the clinical effectiveness of therapeutic cancer vaccines is focused on multiple critical domains, such as detecting immunogenic neoantigens, refining vectors and delivery systems, and overcoming the immunosuppressive tumor microenvironment. The goal of ongoing research is to improve vaccine technology. This includes investigating various expression forms, enhancing co-stimulation elements, and determining appropriate prime-boost strategies [247]. Developing a therapeutic or preventive HIV vaccine is still critically important and will require ongoing research from all scientists [201]. Their widespread use in the HIV vaccine was constrained by safety concerns and their incapacity to produce bNAbs. Consequently, scientists are now focusing more on a few cutting-edge vaccination approaches. The consensus or mosaic immunogens were created by in silico analysis of global HIV-1 sequences to give maximum coverage of viral sequence variety and address the genetic diversity of HIV-1 strains circulating worldwide [202].

In order to prevent unintended reactions, peptide-based vaccinations may also enable the choice of adjuvants that effectively modulate the immune system as needed. Depending on further research, this might be used as a better option than the existing mRNA, viral vector, and dormant entire virus vaccines [249]. Minimum vaccine-associated effects will be crucial as risk–benefit ratios become more contentious as disease prevalence drops. However, achieving zero risk is unachievable, and there will always be a conflict between the imperatives of public health and the regulatory need to mitigate even hypothetical and distant threats [250].

Motivated by their success in COVID-19, BioNtech is developing a vaccine based on mRNA technology and the R21 and PfSPZ vaccines. This strategy might solve the difficulties in developing a malaria vaccine, such as the parasite's ability to evade immune defenses. An mRNA malaria vaccine is anticipated to be very effective, simple to produce, and safe for everyone [251]. Patients with prevalent infections may also be predicted to be free of infections caused by other forms of HPV. Prophylactic HPV vaccinations to prevent disease caused by residual disease or neoplastic cells that persist after therapy have limited scientific validity. Additional research, as well as clinical trials, are required [252]. The future of biomedical science in vaccine development holds promise, with anticipated advancements in personalized medicine, nanotechnology, and artificial intelligence (AI) poised to revolutionize research and clinical practice [253].

The transformative impact of biomedical science on vaccine development is evident through advances in both prophylactic and therapeutic approaches. With significant progress in virology, immunology, and molecular biology, innovations like mRNA vaccines and reverse vaccinology have reshaped how vaccines are designed, making them more effective and allowing rapid responses to emerging health threats. These developments have paved the way for a new era of precision in vaccine creation. Despite these advancements, the journey remains complex. Challenges such as stringent regulatory frameworks, emerging diseases, market uncertainties, and vaccine hesitancy still pose significant hurdles. Addressing these requires a concerted effort from scientists, healthcare professionals, regulators, and global public health organizations. Public education and trust-building initiatives will play a critical role in ensuring broader acceptance and uptake of vaccines. The future of vaccine development looks promising with the integration of cutting-edge technologies like AI, nanotechnology, and personalized medicine. These advancements can revolutionize vaccine production by shortening development timelines, tailoring vaccines to individual needs, and improving overall clinical outcomes. As the field progresses, interdisciplinary collaboration will remain essential to overcoming existing barriers and fostering innovation. By leveraging ongoing scientific breakthroughs, the potential for more efficient, accessible, and effective vaccines becomes increasingly tangible. These innovations promise to improve global health and ensure a more resilient and prepared response to future pandemics and infectious disease threats. The continuous evolution of the biomedical field will be vital in shaping a healthier future for all.

Authors’ contributions

Induni Nayodhara Weerarathna: Conceptualization, Methodology, Data visualization, Writing original draft, Visualization, Creating figures. Elijah Skarlus Doelakeh: Writing- review and editing. Lydia Kiwanuka: Writing- review and editing. Praveen Kumar: Methodology, Review and editing, Visualization, Supervision. Sanvi Arora: Writing- review and editing. All authors have read and approved the final manuscript.

Funding

Open access funding provided by Datta Meghe Institute of Higher Education and Research.

Data availability

Not applicable.

Declarations