Redefining Immunization:

Recent Advances and Innovations in Vaccine Development

 

Sarika Gupta¹*, Victor Alert¹, Arti Gupta²

¹Department of Pharmacy, Agra Public College of Higher Education and Research Centre, Agra – 282007, India.

²Shree Bankey Bihari Dental College and Research Centre, Ghaziabad – 201302, India.

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ABSTRACT:

Vaccines have been a fundamental part of public health for a long time, offering essential protection against infectious diseases. Recent advancements in vaccine technology are now expanding the possibilities of disease prevention and treatment. This article outlines key developments in the field, highlighting novel vaccine technologies, targeted disease treatments, and challenges facing next-generation vaccine efforts. Vaccine development is progressing for traditionally challenging diseases, including HIV/AIDS, various viral infections (e.g., cytomegalovirus, dengue, Ebola), cancer, and other chronic conditions. Efforts also focus on bacterial (e.g., C. difficile, chlamydia, E. coli) and parasitic diseases (e.g., malaria, hookworm, leishmaniasis). Combination vaccines, which simplify immunization schedules, are under development to increase vaccine uptake. The COVID-19 pandemic catalyzed unprecedented collaboration and speed in vaccine development, with the first COVID-19 vaccines authorized within six months. Researchers are now focused on universal COVID-19 vaccines to address multiple variants. Emerging technologies such as nanoparticle-based vaccines and mucosal vaccines (e.g., inhalation or oral delivery) show promise for stronger immunity. Precision vaccine development, drawing on cues from natural immunity, may enhance efficacy and safety. Innovations such as recombinant DNA, viral vector vaccines, non-replicating vector vaccines, RNA vaccines, and DNA plasmid technology are opening new pathways in vaccine development. These technologies aim to create safe and effective vaccines, even for individuals with compromised immune systems. The future of vaccines involves leveraging new technologies and precision approaches to improve safety and efficacy, addressing both current and emerging diseases. Continued research and ethical prioritization in vaccine development will be crucial for enhancing global health outcomes.

 

 

 

INTRODUCTION:

Vaccines that have been created over the two centuries since Jenner’s time, there have been able to achieve remarkable reductions in the incidence of disease and infection in every place they have been administered. Attenuation and inactivation were two of Pasteur's early ideas for making vaccines, are still at the two ends of vaccine technology today^1,2.

 

Vaccines are biological substances that provoke an immune response to a particular antigen from a pathogenic organism responsible for infectious diseases. In 1796, Edward Jenner made the first vaccine against smallpox by using cowpox as an inoculant. The official eradication of smallpox was declared in 1980, thanks to his revolutionary efforts. Vaccines have helped eliminate various infectious illnesses, including polio, from several countries spanning North and South America, in addition to Europe. As vaccines continue to be used, it is easy to think that additional contagious diseases would immediately follow. Regrettably, we have made significant progress in the wrong direction with the rise of the anti-vaccine movement and the decline in vaccine acceptance³.

 

Each year, vaccines save millions of lives from infectious diseases. Meanwhile, Conditions preventable with vaccines claim the lives of millions of people^4,5. These days, it is possible to directly create reduced virulence mutants express using live vectors to present vaccine proteins, purifying and synthesizing microbial antigens, and modifying DNA, RNA, proteins, and polysaccharides to induce a range of immune responses. These advancements are made possible by the refinement of microbial elements, genetic alterations, and better knowledge of immune protection mechanisms. Vaccinology currently addresses both infectious and non-infectious ailments. The proliferation of new vaccines makes it possible to target new populations for vaccination and necessitates the creation of administration ways other than injection. These developments also bring with them new challenges in the manufacturing, distribution, and regulation of vaccines^1-6.

 

The introduction of vaccines as immunotherapy involves specific antigens to stimulate controlled immune responses, leading to robust and often targeted long term immunity. Vaccines are pivotal in inducing potent immunity against infectious agents, significantly impacting human health by eradicating harmful pathogens. In the realm of cancer treatment, therapeutic vaccines are designed to provoke tumor-specific adaptive immune responses, focusing on treating cancer rather than solely preventing it like traditional vaccines. These therapeutic vaccines are under extensive research to enhance their effectiveness in combating cancer by addressing challenges such as immune tolerance, the tumor microenvironment, and immune effector cell activation^7,8.

 

Mechanism:

We must comprehend how the body combats illnesses. The body's immune system reacts to illnesses like influenza, commonly referred to as the "flu," which are brought on by bacteria and viruses. In order to eliminate the invasive microbes and any contaminated cells, white blood cells are triggered. However, when the immune system is initially exposed to a certain disease, it may take more than a week for it to create a defence. Before the immune system has a chance to react, some illnesses can cause harm or even death because they develop quickly. Fortunately, when white blood cells encounter a disease, they gain immunological memory. When infected with the same disease again, the immune system promptly recognizes and destroys the germ, preventing symptoms. Antigens are distinct molecular patterns seen on the surface of microorganisms that resemble fingerprints. These antigens are specially recognized by the body's white blood cells as "foreign." White blood cells are activated to create antibodies as a result. Specialized proteins called antibodies bind to the antigens on the surface of microorganisms, triggering an immune response to defend against and eliminate them⁹.

 

These contain immunogens that antigen-presenting cells process and exhibit to CD4+ T cells, stimulating humoral and cellular immune reactions, encompassing antibody generation and the activation of CD8+ T cells¹⁰. Live vaccines offer greater effectiveness than killed vaccines by retaining more antigens, while toxoids like those for tetanus and diphtheria are bacterial vaccines that are based on the inactivation of exotoxins. Subunit vaccines- such as hepatitis B and meningococcal vaccines, are effective when conjugated to carrier proteins like tetanus toxoid, enhancing their efficacy¹¹. In response to non-peptidic antigens, there is no T-cell presentation, class switching, or memory T-cell formation, yet adjuvants can improve antibody synthesis and T-cell activity¹².

 

Vaccines function by simulating a specific sickness. During vaccination, a modified form of a pathogenic bacterium or toxin is introduced to the body that is incapable of growing or causing symptoms. The inoculation does, however, display the signature antigens that define a specific virus or bacterium. As a result, the immune system reacts similarly to the disease-causing bacterium or toxin in its natural state. It creates a reaction and learns to recognize the antigens from the germs in the vaccine, so that, upon later exposure to the active pathogen, the body recognizes it as a threat and quickly works to remove it.

 

When vaccinated, a modified version of a virus or bacterium is introduced into the body (left). This vaccine activates the immune system, prompting it to generate antibodies specific to the microorganism (center). This readies the immune system to identify the microorganism, consequently if the body faces the live pathogen later, it can quickly produce antibodies that bind to the microorganisms, preventing infection.

 

Figure 1: Vaccine immunity

 

Table 1: Various steps of vaccines involved with their mechanism

Steps	Mechanism
1.Antigen Introduction	Vaccines contain immunogenic peptides that antigen-presenting cells engulf, process, and expose with MHC stimulating molecules to CD4+ T cells. This engagement initiates humoral plus cellular immune responses, including induction of antibodies, CD8+ T cell activation, and macrophage stimulation. Memory cells are formed during this process, enabling a swift response to future exposures to the antigen.
2.Antibody Production	To protect against infectious diseases, B cells evolve into plasma cells, which synthesize targeted antibodies. This immune response involves antibody production to combat diseases like meningitis and pneumonia. Adjuvants, such as aluminum salts, enhance antibody synthesis and T-cell responses, stimulating immune responses.
3.Immune Memory	The immune system learns to identify vaccine antigens, forming memory cells that can quickly multiply upon re-exposure. This memory enables a rapid and effective immune response if the body later encounters the actual disease-causing microorganism12,13.

 

Benefits and Drawbacks of Vaccines

Table 2: Summarizes vaccines aspects with its benefits and drawbacks

Aspect/ Vaccine Platform	Benefits	Drawbacks
Toxoid	Non-virulent, robust, and shelf-stable	Require regular booster doses, local site reactions14
Inducible Immunity	Prevents infectious diseases	Side effects like infections, allergies, and adverse reactions14
Eradication of Diseases	Smallpox vaccine led to disease eradication	Inactivated vaccines may require boosters; Live attenuated vaccines can restore virulence15,16
Vaccine Platforms	Various platforms offer high immunogenicity, lasting immunity, and ease of preparation	Potential risks like infection, cold chain storage, and immunocompromised suitability16
Global Health Contribution	Prevents epidemics and pandemics; Protects individuals against diseases	May not offer complete immunity; Ingredients may be unacceptable for some17,18
Attenuated	Attenuated vaccines preserve native antigens, closely mimicking natural infection and generating a strong B and T cell response.	However, they carry a risk of causing infection, require cold chain storage, and are unsuitable for immunocompromised individuals.
Inactivated	This vaccine type elicits a strong immune response, with a greater activation of B cells compared to T cells. It is safer than live attenuated vaccines and offers stable manufacturing and distribution.	The inactivation process may alter epitopes, potentially impacting immune recognition.
Viral Vector	Vigorous immune response, preservation of the antigen’s natural configuration	Manufacturing is complex, with risks of genomic integration, and the immune response may be weakened by pre-existing immunity19

 

THE DIFFERENT MODES OF ADMINISTRATION OF VACCINES:

Most vaccines available today are administered via injection, either into the fatty layer beneath the skin or directly into muscle. Some vaccines have also been formulated for oral use, making them easier to administer. However, this approach isn’t suitable for all types of vaccines, as the digestive system may alter the antigens. Since early 2014, the influenza vaccine for children is the only one that can be administered nasally, delivered as a spray inhaled through normal breathing. Jet injectors, which use high-pressure streams of liquid to penetrate the skin and reach underlying tissue, were initially used in the 1940s and have since been refined through the late 20th and early 21st centuries to enhance their effectiveness with vaccines²⁰.

 

(a)           Oral administration This involves giving vaccines through the mouth, such as Rotavirus vaccines and typhoid vaccines

(b) Intranasal administration This involves administering vaccines through the nose, commonly used for live, attenuated influenza vaccines.

(c)  Subcutaneous-administration This involves-injecting vaccines into the fat beneath the skin

(d) Intramuscular-administration This involves-injecting vaccines directly into-muscle, which is the most common method for many vaccines.

(e)  Mucosal immunization This includes intraocular, intranasal, and/or oral administration, which targets the mucous membranes to stimulate an immune response.

(f)  Intraocular administration This involves administering vaccines directly into the eye which is a less common method.

 

Factors such as vaccine type, the recipient’s age and health, and the required immune response influence the choice of administration route. Each route has its advantages and disadvantages, and healthcare professionals must be trained to administer vaccines safely and effectively²¹.A harmful pathogen elicits two distinct responses within our body. The initial response presents with symptoms such as fever, -nausea, vomiting, -diarrhea, -and-rash. The immune system’s reaction to the infection is the second step. Gradually, as the immune system becomes more effective, it reduces the number of pathogens, leading to the disappearance of symptoms. Vaccines contain either the whole microorganism that causes disease or its harmless components²².

 

Development Process of Vaccines:

The initial step in vaccine development involves cultivating a modified form of the microorganism responsible for the disease. This modification allows the immune system to recognize it without causing harm.

 

Live-attenuated vaccines are created from live microorganisms that have been weakened so they don’t cause illness. These vaccines are highly effective in stimulating an immune response, as they closely resemble a natural infection. However, they may not be suitable for people with suppressed immune systems, such as individuals with HIV or undergoing-chemotherapy. Additionally, these vaccines require refrigeration, making them less practical in areas without reliable cooling facilities.

 

Inactivated vaccines these-vaccines use viruses-or bacteria that-have been rendered inactive through chemicals, -radiation, -or-heat. These-vaccines-are less prone to degradation than live-attenuated ones and do not need refrigeration, making them easier to distribute. However, they are less effective at stimulating the immune system compared to live-attenuated vaccines, so booster doses may be necessary after a few years.

 

Sub-unit vaccines contain specific antigens from a microorganism that can trigger an immune response. A less common type, known as toxoid vaccines, is made from the toxins produced by microorganisms instead of using parts of the microorganism itself.

 

As of early 2014, several new vaccination methods were under research, including DNA vaccines, which involve injecting DNA containing genetic instructions to produce antigens. The body’s cells then generate these antigens, triggering an immune response similar to that of a traditional vaccine. Another approach being developed was vector vaccines, which use harmless viruses or bacteria to deliver DNA encoding antigens of disease-causing organisms. These vectors mimic infection without causing illness, allowing the immune system to recognize the antigens. Additionally, many vaccines contain extra components like aluminum-based adjuvants, which boost immune response by helping the body identify antigens more effectively, as well as stabilizers or preservatives to extend shelf life and improve storage²³.

 

VACCINE’S CATEGORIES:

Table 3: Summarizing of vaccines of different categories^24-30

Vaccine-	Examples	-Advantages	-Disadvantages
Live-Attenuated	-Measles, mumps, rubella (MMR) vaccine -Oral polio vaccine (OPV) -Varicella (chickenpox) vaccine	-Provides robust and durable immunity -Only requires 1-2 doses	- May cause mild symptoms of the disease -Not suitable for those with weakened immune systems (Indian science)
Inactivated/Killed	-Influenza vaccine -Hepatitis A vaccine -Polio vaccine (IPV)	-Safer for those with weakened immune systems -Can be used in pregnant women and infants	-Require multiple doses to build immunity -Immunity may not be as long-lasting
Subunit	-Hepatitis B vaccine -HPV vaccine -Acellular pertussis vaccine	-Safer for those with weakened immune systems -Can be used in pregnant women and infants	-May require adjuvants to boost immune response -Immunity may not be as long-lasting
Toxoid	-Diphtheria vaccine -Tetanus vaccine	-Safer for those with weakened immune systems -Can be used in pregnant women and infants	-May require multiple doses to build immunity
Conjugate	-Haemophilus influenzae type b (Hib) immunization -Pneumococcal conjugate (PCV) immunization	-Effective in infants and young children -Can be used in those with weakened immune systems	-May require multiple doses to build immunity
mRNA	-COVID-19 vaccine by Pfizer-BioNTech -COVID-19 vaccine by Moderna	-Can be rapidly developed and manufactured -Highly effective with fewer doses	-Newer technology, long-term safety data still being collected
DNA Vaccines	-Therapeutic vaccines against cancers like cervical cancer	can encode various viral/bacterial antigens-Relatively cost-effective to produce strong and long-lasting immune responses	-Requires technical improvements like gene optimization, novel formulations, and delivery methods to enhance potency

 

Vaccines used in cancer immunotherapy:

i.    Autologous Vaccines: These vaccines are derived from the patient’s own cancer cells, which are extracted, processed, and then re-administered to stimulate an immune response against the cancer³¹.

ii.   DNA Vaccines: These vaccines utilize DNA linked to antigens associated with tumors to stimulate a targeted immune response against a current tumor. They trigger the body’s cells to produce unique tumor antigens, directing immune cells to recognize and target those antigens on existing cancer cells^32-34.

iii. Allogenic-Vaccines: These vaccines are created using non-self cancer cells that are cultured in a laboratory, making them less expensive to develop and produce compared to autologous vaccines^35,36.

 

Figure 2: Different vaccines are employed in cancer immunotherapy to stimulate the immune system to recognize and attack cancer cells, providing a potential treatment option for different types of cancer^37,38.

 

MARKETED VACCINES:

Table 4: List of marketed vaccines^39,40

Vaccine	Category	Targeted Organ	Method	Constituents
COVID-19 Vaccine (mRNA)	COVID-19	Respiratory system	mRNA technology	mRNA blueprint encoding the SARS-CoV-2 spike protein
COVID-19-Vaccine (adenovirus vector)	COVID-19	Respiratory system	Adenovirus vector	Adenovirus vector engineered to produce the SARS-CoV-2 spike protein
Influenza-Vaccine (inactivated)	Seasonal Influenza	Respiratory system	Inactivated influenza viruses	Inactivated influenza A and B viruses
Influenza Vaccine (live, attenuated)	Seasonal-Influenza	Respiratory system	Live, modified influenza viruses	Live, attenuated influenza A and B viruses
Influenza Vaccine (recombinant)	Seasonal Influenza	Respiratory system	Recombinant influenza proteins	Recombinant influenza hemagglutinin
Hepatitis A Vaccine	Hepatitis A	Liver	Inactivated hepatitis A virus strain	Inactivated hepatitis A virus
Hepatitis B Vaccine	Hepatitis-B	Liver	Hepatitis B surface antigen produced via recombinant technology	Recombinant hepatitis B surface antigen
Hepatitis A and B Vaccine	Hepatitis A and B	Liver	Inactivated hepatitis A virus and recombinant hepatitis B surface antigen	Inactivated hepatitis A virus and recombinant hepatitis B surface antigen
Human Papillomavirus Vaccine	HPV	Genital area	Recombinant HPV proteins	Recombinant HPV L1 proteins
Meningococcal Conjugate Vaccine	Meningitis	Meninges	Conjugated meningococcal polysaccharides	Conjugated meningococcal polysaccharides
Pneumococcal Conjugate Vaccine	Pneumonia	Lungs	Conjugated pneumococcal polysaccharides	Conjugated pneumococcal polysaccharides
Pneumococcal Polysaccharide Vaccine	Pneumonia	Lungs	Pneumococcal polysaccharides	Pneumococcal polysaccharides
Measles, -Mumps, plus Rubella Vaccine	Measles, -Mumps, plus Rubella	Various organs	Live, modified live viruses	Live, attenuated measles, -mumps, plus rubella viruses
Tetanus plus Diphtheria-Toxoids Vaccine	Tetanus plus- Diphtheria	Nervous system plus respiratory system	Inactivated tetanus plus- diphtheria-toxoids	Inactivated tetanus plus diphtheria toxoids
Varicella-Vaccine	Chickenpox	Skin	Live, attenuated-varicella-virus	Live, attenuated-varicella virus
Zoster-Vaccine, Recombinant	Shingles	Skin	Recombinant-varicella-zoster-virus-glyco-protein E	Recombinant-varicella-zoster-virus-glyco-protein E
Haemophilus-influenzae-type b Vaccine	Haemophilus- influenzae type b	Respiratory system	Conjugated Haemophilus - influenzae type b polysaccharides	Conjugated Haemophilus-influenzae type b polysaccharides
Mpox Vaccine	Mpox	Skin	Live, attenuated mpox virus	Live, attenuated mpox virus
Respiratory---- Syncytial-Virus—Vaccine	Respiratory---- Syncytial-Virus	Respiratory system	Various RSV antigens	Various RSV antigens

 

Marketed vaccines used in immunotherapy:

Table 5: vaccines used in immunotherapy^41-42

Vaccine	Category	Targeted Organ	Method	Constituents
Sipuleucel-T (Provenge®)	Prostate Cancer Vaccine	Prostate	Autologous dendritic cells loaded with a recombinant fusion protein	Autologous dendritic cells and recombinant fusion protein
mRNA Vaccine against Pancreatic Cancer	Pancreatic Cancer Vaccine	Pancreas	mRNA technology	Custom-made mRNA vaccine
Therapeutic Vaccine against HPV-associated Head and Neck Cancers	Head and Neck Cancer Vaccine	Head and Neck	Therapeutic vaccine based on proteins found in HPV	Proteins found in HPV

 

NOVEL VACCINE TECHNOLOGIES:

There is an increasing emphasis on creating innovative vaccines that can elicit safe and effective immune responses, even in individuals with compromised immune systems. The advent of new technologies and research, including recombinant DNA, viral vector vaccines, non-replicating vector vaccines, RNA vaccines, and DNA plasmid technology, has led to exciting breakthroughs and new possibilities in vaccine development⁴³.

 

i. Targeting Difficult-to-Treat Diseases

Several new vaccines under development are aimed at treating challenging diseases, such as HIV/AIDS, viral infections (like cytomegalovirus, dengue, and Ebola), cancer, Alzheimer's disease, rheumatic disorders, bacterial infections (such as Clostridium difficile, chlamydia, and E. coli), and parasitic diseases (including malaria, hookworm, and leishmaniasis)^44,45.

 

ii. Combination Vaccines

Several combination vaccines are being developed, offering practical merits that can boost vaccine uptake and improve public health

 

(a). COVID-19 Vaccine:

The COVID-19 pandemic has brought the world together in the pursuit of a vaccine, leading to the authorization of the first COVID-19 vaccine within just six months. There is a pressing need to leverage recent scientific advancements to create improved COVID-19 vaccines, and numerous research teams are exploring the concept of a universal vaccine to protect against multiple virus variants^46-49.

 

(b). Polio Eradication vaccine:

Thanks to coordinated global efforts to eradicate polio, there has been a 99.9 % reduction in cases worldwide a with the disease now remaining endemic in only two countries. Inactivated vaccines must be entirely safe and non-infective. In the past, field outbreaks have occasionally been linked to incomplete inactivation, an issue that could be avoided by using more dependable inactivating agents, inactivation procedures, and rigorous safety testing during production. Additionally, the production of these vaccines involves culturing large amounts of the infectious agent, posing potential risks to manufacturing staff and the environment. Vaccines produced in eggs, tissue culture, or other media may contain unintended "foreign" proteins, which could influence immunogenicity or carry allergenic/reactogenic risks. Lastly, inactivated vaccines have limitations in their mode of delivery, impacting the type and duration of immune response they trigger. To improve their immunogenicity and effectiveness, adjuvants or immune stimulants may be needed to enhance the immune response. Attenuated vaccines must be carefully regulated and well-characterized to ensure they deliver effective protective immunity without causing notable symptoms in the host animal. There is a small risk that the attenuated antigen could revert to full virulence, making it essential to conduct thorough safety studies on reversion risks. Additionally, during the culturing of the vaccine antigen, other infectious agents may unintentionally be introduced, potentially causing unwanted side effects when the vaccine is deployed in the field^50-53.

 

FUTURE PROSPECTIVE OF VACCINES:

i. Nanoparticle-based vaccines- are a promising technology for COVID-19 and future vaccines

ii. Mucosal vaccines- administered via inhalation or oral routes could induce strong mucosal immunity (IgA) and systemic immunity (IgG, IgA, T-cells) Peptide-directed phage particles administered by inhalation can elicit a systemic humoral response^54,55.

 

Efforts are ongoing to develop more effective cancer vaccines, with emerging technologies like alternative delivery techniques and nano vaccine technology showing promise Maximizing individual protection against breakthrough infections with COVID-19 vaccines could help decrease disease severity and transmission risk⁵⁶.

 

Some challenges and future considerations are Globally, many SARS-CoV-2 variants have emerged, even just a year after the initial vaccines were developed There have been some controversies regarding the data and trials for certain COVID-19 vaccines. Severe side effects, while extremely rare, still need to be thoroughly investigated to prevent future occurrences^57,58.

 

iii. Accelerating Vaccine Development

Its development is crucial for disease prevention at global level. Precision vaccine development using cues from natural immunity could help design more effective vaccines. Formulating future vaccines requires going beyond just antigens and adjuvants. Precision vaccine design and formulation will be key to combating both current and future infectious diseases^1,59,60.

 

CONCLUSION:

Vaccines are indispensable in public health by averting infectious disorders and have been a cornerstone of disease prevention strategies. The development and approval of vaccines involve rigorous testing processes to ensure safety and efficacy before regulatory authorities like the US-FDA grant endorsement for public use. Vaccines undergo extensive testing, starting from cell cultures to animal studies before progressing to human trials in three phases to assess safety and effectiveness.

 

Furthermore, prioritizing vaccine development projects involves considering factors such as global health benefits, affordability, disease burden, and potential synergistic interactions with other diseases. The decision-making process for vaccine development also includes ethical considerations. Vaccines have emerged as a promising immunotherapeutic strategy for cancer treatment. Several types of cancer vaccines, including Nanovaccines, mRNA vaccines, and dendritic cell (Dc) vaccines, have demonstrated the ability to elicit robust immune responses against malignant growths in preclinical studies and therapeutic trials. Nanovaccines offer advantages such as targeted delivery, enhanced immunogenicity, and the ability to incorporate multiple antigens and adjuvants. mRNA vaccine are attractive due to their high potency, specificity, versatility, rapid development, and safety.

 

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Received on 11.11.2024      Revised on 18.12.2024 Accepted on 17.01.2025      Published on 03.03.2025 Available online from March 10, 2025 Res.  J. Pharma. Dosage Forms and Tech.2025; 17(1):73-81. DOI: 10.52711/0975-4377.2025.00011 ©AandV Publications All Right Reserved
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