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Vaccinology (Lead Section)

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Vaccinology, also known as the science of vaccines, is a scientific study to understand the development of vaccines starting from researching the technology, delivery strategies, clinical evaluations, to the safety, regulation, ethical and economic considerations of vaccines[1]. Introductory overview of vaccines, features of vaccine protection, the safety and side effects, challenges to vaccination success, and its future development will be covered[2]. Vaccines take advantage of the ability of the human immune system to respond, remember, and encounters pathogen antigens[2]. Improved understanding of the immunological basis for vaccination are needed to develop vaccines for hard-to-target pathogens and antigenic variable pathogen [3], to control outbreaks [4][5], to work out how to revive immune responses in the aging immune system[6], and to protect the growing population of older adults from infectious diseases. B cells that produce antibodies (humoral immunity) and T-cells mediate the adaptive immune response (cellular immunity)[2]. All vaccines currently in use are thought to primarily protect by inducing antibodies. When confronted with a pathogen, an individual whose immune system has been vaccinated against that pathogen can mount more rapidly and robust protective immune response[7]. Vaccines are typically created to protect against clinical manifestations of infection[8]. Some vaccines, in addition to preventing disease, may also protect against asymptomatic infection or colonization, reducing pathogen acquisition and thus its onward transmission, thereby establishing herd immunity[9]. The safety and side effects of vaccines are safe as interventions to defend human health based on existing data. Common side effects are documented in clinical trials and rare side effects are tightly controlled and robust post-marketing surveillance systems are in placed[2]. The challenges to vaccination success are ensuring that the strong headwinds against the deployment, ranging from poor infrastructure and lack of funding to vaccine hesitancy and commercial priorities, do not prevent protection in society[2]. For future development, vaccines are needed for important diseases to reduce morbidity and mortality, which are likely to affect both high-income and low-income countries, including vaccines for meningitis, RSV, and CMV. New vaccines to combat hospital-acquired infections are also needed, especially with antibiotic-resistant Gram-positive bacteria that are associated with wound infections and intravenous catheters and various Gram-negative organisms[2].

Overview of Vaccines

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Vaccines take use of the capacity of the human immune system to respond, recall, and confront disease antigens[2]. Improved understanding of the immunological basis for vaccination is required to develop vaccines for difficult-to-target pathogens and antigenic variable pathogens[3], control outbreaks [4][5], figure out how to revive immune responses in the aging immune system[6], and protect the growing population of older adults from infectious diseases. Effectively communicating the science of vaccination to a skeptical audience is a challenge for all those involved in vaccine immunobiology[10]. This can only be accomplished by being open about what is known and doesn't know, as well as proposing solutions to close current knowledge gaps. A vaccine is a biological substance that may be used to safely produce an immune response that protects against infection and/or sickness when exposed to a pathogen in the future. Most vaccines require one or more protein antigens to elicit immune responses that give protection. Vaccines are often classed as either live or non-live (also known as 'inactivated')[2]. Live vaccines include attenuated reproducing strains of the dangerous organism in question. Non-live vaccinations are safe for immunocompromised people, although vaccines may not protect those with combined immunodeficiency. Live vaccines reproduce well enough to elicit a robust immune response but are not sufficient to generate major disease symptoms[2]. Some safe, live attenuated vaccinations take numerous doses and generate only brief protection. To boost their capacity to elicit an immune response, non-live vaccinations are frequently coupled with an adjuvant (immunogenicity). For more than 80 years, aluminum salts have been utilized as an adjuvant in vaccinations. Adjuvants based on liposomes and oil-in-water emulsions are important. Other ingredients in vaccines serve as preservatives, emulsifiers, or stabilizers[11][12].

Figure 1: The impact of vaccination on selected diseases in the UK. Vaccination against infectious diseases such as diphtheria (part a), capsular group C meningococcus (part b), polio (part c), Haemophilus influenzae type B (part d), measles (part e), and pertussis (part f) resulted in a significant reduction in their incidence.[2]

Vaccines Induce Antibodies

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Except for BCG (which is considered to elicit T-cell responses that prevent severe illness), all vaccinations now in use are assumed to primarily give protection through the development of antibodies. There is substantial evidence that diverse forms of functional antibodies play a crucial role in vaccine-induced protection[2]. There is substantial evidence that diverse types of functional antibodies helps in vaccine-induced protection, and this evidence comes from three primary sources: immunodeficiency states, passive protection studies, and immunological data[2].

Immunodeficiency States

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Individuals with complement deficits are especially vulnerable to infections. Pneumococcal illness is more frequent in those who have a weakened spleen[13]. Individuals who lack antibodies are vulnerable to the varicella-zoster virus (which causes chickenpox) and other viral illnesses. Once infected, individuals have the same ability to control the illness as an immunocompetent person[14].

Passive Protection

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Exogenous antibody infusions either intramuscularly or intravenously can give protection against some illnesses[15][16]. The passive transmission of maternal antibodies through the placenta is the example[17]. Vaccination of pregnant women against group B streptococci and the respiratory syncytial virus has not been proved to prevent neonatal or newborn illness[18].

Immunological Data

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Polysaccharide vaccines are created by using the surface polysaccharides of invasive bacteria such as meningococci and pneumococci[19]. These vaccines do not elicit T-cell responses because the vaccines protect through antibody-dependent pathways[20]. The vaccination induces T-cells to detect the protein carrier (a T-cell-dependent antigen), and these T-cells assist B cells[21].

Vaccines Needs T-Cell Help

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Except for their involvement in assisting B cell growth and antibody production, T-cells' role in defense is little understood. Failure to control a pathogen after infection is caused by T-cell insufficiency. The relative reduction of T-cell responses that occurs at the end of pregnancy makes infection with influenza and varicella-zoster viruses more severe[22]. There are little evidence that T-cells have a role in vaccine-induced immunity. T-cells have traditionally been classified as either cytotoxic (killer) or helper T-cells[23]. From studies, sterilizing immunity against S. pneumoniae carriage may be produced by transplanting T-cells from mice exposed to S. pneumoniae.

Feature of Vaccine Protection

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The adaptive immune response is mediated by B cells that produce antibodies (humoral immunity) and T-cells (cellular immunity)[2]. All currently used vaccines are thought to primarily protect by inducing antibodies. When confronted with a pathogen, a person whose immune system has been immunized against that pathogen can mount a more rapid and robust protective immune response. Vaccines are typically developed to protect against clinical manifestations of infection[8]. Some vaccines, in addition to preventing disease, may also protect against asymptomatic infection or colonization, reducing pathogen acquisition and thus its onward transmission and, as a result, establishing herd immunity[9]. Vaccines are created to protect against clinical manifestations of infection. vaccines may also help to prevent asymptomatic infection or colonization. The most important feature of immunization programs is the induction of herd immunity. Each dose of vaccine protects many more people than the person who receives it[2].

Figure 2: Vaccines of various types. A schematic representation of various types of pathogen vaccines.[2]

Immune Memory

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When confronted with a pathogen, the immune system of a person who has been vaccinated against that pathogen can mount a quick protective immune response. When the incubation period is long enough for a new immune response to develop, immune memory is sufficient for protection against pathogens. In the case of HBV, for example, a vaccinated individual is protected even if the virus is exposed sometime after vaccination and the levels of vaccine-induced antibodies have already waned. Because the primary burden of some infections is in young children, no further boosting is done after the second year of life. It is well known that giving children five or six doses of tetanus[24] or diphtheria[25] vaccine provides lifelong protection[26]. Most vaccines are designed to protect against disease in infancy and are administered to infants, adolescents, and pregnant women. Many countries in high-income countries have switched to the acellular pertussis vaccine, which is less reactogenic than (and thus thought to be preferable to) the older whole-cell vaccine[27]. Breakthrough cases are less likely in people who have received two doses of the measles–mumps–rubella vaccine or the varicella-zoster vaccine[28]. Following a single dose of some live attenuated viral vaccines, such as the yellow fever vaccine, it appears that lifetime protection is the rule. To avoid cross-reactive immune responses from different strains, vaccines must be able to include as many different strains of the same pathogen as possible[29].

Herd Immunity

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Herd immunity, or more accurately 'herd protection,' is an important component of vaccine-induced protection[30]. Vaccines cannot directly protect every individual in a population because some people do not get vaccinated for a variety of reasons. Vaccination, on the other hand, prevents not only the disease development but also infection[31]. To prevent outbreaks of highly transmissible pathogens such as measles or pertussis, approximately 95 percent of the population must be immunized[32]. A lower percentage of vaccine coverage may be sufficient to have a significant impact on disease for less transmissible organisms. Apart from the tetanus vaccine, all other vaccines induce some degree of herd immunity. This substantially enhances population protection beyond that which could be achieved by vaccination of the individual only[33]. Vaccination of children and young adults with capsular group C meningococcal vaccine resulted in almost complete elimination of disease from the UK in adults as well as children.

Prevention of Infection Versus Disease

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It is difficult to determine whether vaccines prevent infection or disease development after pathogen infection[34]. Improved comprehension could have significant implications for vaccine design. BCG vaccination can be used to demonstrate this point because there is some evidence that it can help prevent both disease and infection[35]. A vaccine that could also prevent the virus SARS-CoV-2 from being acquired and thus prevent both asymptomatic and mild infection would have a much larger impact by reducing community transmission.

Non Specific Effects

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Some vaccines disrupt the immune system in such a way that general changes in immune responsiveness occur, potentially increasing protection against unrelated pathogens[36]. In humans, this phenomenon has been best described in relation to BCG and measles vaccines, with studies showing significant reductions in all-cause mortality[37]. It is unclear how current immunization schedules could be modified to improve population protection via non-specific effects.

Safety and Side Effects

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Vaccines' safety and side effects as interventions to protect human health are safe, according to extant research. Many countries have post-marketing surveillance systems in place, and common adverse effects are documented in clinical studies. Rare side effects are rigorously regulated[2].

Common and Rare Side Effects

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A new vaccine's approval necessitates safety trials involving anywhere from 3,000 to tens of thousands of people[38]. Many vaccines have adverse effects such as injection site pain, redness, and swelling, as well as systemic symptoms including fever, malaise, and headache. People with known allergies (such as egg or latex) should avoid vaccines that may have traces of these products left over from the production process. Anaphylaxis is the most common of these rare side effects for parenteral vaccines, occurring after fewer than one in a million doses[39]. After measles immunization, there is an extremely low incidence of idiopathic thrombocytopenic purpura (1 in 24,000 vaccine recipients)[40]. Vaccines or their components do not appear to cause autism. It's critical to keep monitoring vaccination safety after it's been approved to catch unusual and long-term side effects.

Immunodeficiency and Vaccination

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The majority of vaccinations currently in use are inactivated, purified, destroyed organisms, pathogen protein, or polysaccharide components[41]. The use of these vaccines poses no risk to immunocompromised people. Yellow fever vaccine is not recommended for people who have T-cell immunodeficiency since it can induce severe viscerotropic or neurotropic sickness[42].

Antigenic Overload

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Vaccines only cover a small percentage of the antigens that children are exposed to in their daily lives[43]. Children who received immunizations had a similar or even lower risk of unrelated infections in the later period, according to studies[44]. In terms of previous antigen exposure through vaccination, there was no difference.

Challenges to Vaccination Success

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The challenges to vaccination success are ensuring that the strong headwinds against the deployment, ranging from poor infrastructure and lack of funding to vaccine hesitancy and commercial priorities, do not prevent successful protection of the most vulnerable in society[2]. Although limited knowledge about which antigens are protective, which immune responses are required for protection, and how to enhance the appropriate immune responses, particularly in the elderly, are important considerations, these are not traditional scientific challenges[2].

Access to Vaccine

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Access to vaccines remains the most significant barrier to human population protection through vaccination. Vaccine access is currently restricted in various ways across the globe. Vaccine coverage has plateaued, with only 86 percent of people receiving diphtheria–tetanus–pertussis vaccines[45]. The Vaccine Alliance provides funding to aid in the introduction of new vaccines in the world's poorest countries. It has significantly accelerated access to new vaccines that were previously only available in high-income countries[46]. However, countries that do not meet the criteria for Gavi funding will face significant financial difficulties. Most vaccines must be kept at 2–8°C, which necessitates cold storage infrastructure and a cold chain to the clinic where the vaccine is administered, both of which are lacking in many low-income countries[47]. Oral vaccines (such as rotavirus, polio, and cholera) and nasal vaccines can be administered quickly and on a large scale by less-skilled personnel.

Commercial Viability

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Orphan vaccines are those that are being developed for diseases for which there is no commercial incentive[48]. These are diseases with a limited geographic spread of outbreaks that occur on a sporadic basis. The Coalition for Epidemic Preparedness Innovations is expected to play a significant role in the development of vaccines for these pathogens[48].

Immunological Challenges

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Some vaccines are likely to find a commercial market, but the development of new vaccines faces immunological challenges. Pathogens with a wide range of symptoms, such as HIV and hepatitis C, present a unique challenge. Vaccines in development could target different stages of the parasite's life cycle or multiple stages of the parasite's life cycle[49]. In high-income countries, seasonal influenza vaccines have been used to protect vulnerable people. Vaccines are made from viruses grown in eggs and take about 6 months to make[50]. Their efficacy varies from season to season, partly due to the difficulty in predicting which virus strain will be circulating. The optimal characteristics of a prophylactic TB vaccine, which antigens should be included, and the nature of protective immunity remain unknown[51]. A viral vector expressing a TB protein, 85A, has been tested in a large TB-prevention trial in South Africa but this vaccine did not show protection.

Future Development

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For future development, vaccines are needed for several important diseases to reduce morbidity and mortality, which are likely to affect both high-income and low-income countries, including vaccines for meningitis, RSV, and CMV. New vaccines to combat hospital-acquired infections are also needed, especially with antibiotic-resistant Gram-positive bacteria that are associated with wound infections and intravenous catheters and various Gram-negative organisms[2]. There are several diseases for which new vaccines are required to reduce morbidity and mortality. Vaccines against group B Streptococcus, RSV, and CMV are in the works[52]. The impact of a licensed RSV vaccine on infant health and pediatric hospital admissions would be enormous. Another important area of research is the fight against hospital-acquired infections, particularly antibiotic-resistant Gram-positive bacteria (such as Staphylococcus aureus) that cause wound infections[53]. In this field, progress has been slow, and targeting products to at-risk patient groups before hospital admission or surgery will be a key consideration. Infection prevention in the elderly should be a public health priority. A major challenge is gaining a better understanding of immunosenescence and how to improve vaccine responses[54]. By 2050, the proportion of people aged 60 and up is expected to rise from 12 percent to 22 percent[55]. Advances in immunology, systems biology, genomics ,and bioinformatics offer opportunities to improve our understanding of immune responses by vaccines. The pathogen genetic sequence alone can be used to build next-generation vaccines, significantly speeding up the development and manufacturing processes[56]. The target pathogen antigen is expressed by a recombinant virus whose genome has been altered to express the target pathogen antigen. The target antigens are encoded by DNA or RNA in nucleic acid-based vaccines[57]. In the event of an emerging pathogen, vaccines are versatile and quick to adapt and produce. The novel RSV vaccine DS-Cav1 is a example of how immunological insight can revolutionize vaccine development[58]. Innovative new vaccine platforms are being developed to enhance and skew the immune response to pathogens against which traditional vaccine approaches have failed. Innovative delivery methods, such as microneedle patches, are also being developed, with potential advantages of ease of delivery with minimal pain and safer administration and disposal[59].

References

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