Immunization and infectious disease

• ALSO KNOWN AS: Vaccination

Definition

Immunization, also known as "vaccination," is the administration of a substance (a vaccine) through inoculation, ingestion, or nasal inhalation to stimulate a person’s immune system and aid it in fighting a particular disease. Persons who receive a vaccine are considered immunized against a particular pathogen.

Introduction

The period from 1870 to the start of World War I is considered to have been the golden age of immunology. During this time, French chemist and pharmacist Louis Pasteur discovered proof of the germ theory of disease, Russian zoologist Élie Metchnikoff, the "father of innate immunity," proposed the cellular theory of immunity, and several important new vaccines became available, many developed by Pasteur himself.

Vaccination remains the most important protection against viral infections, especially because of the lack of effective treatment options once a viral infection is established. Similarly, there is renewed interest in vaccine development internationally due to the decreasing effectiveness of antibiotics in treating bacterial infections.

No useful vaccines yet exist against fungal diseases such as candidiasis, chlamydia, helminthiasis (parasitic worm infection), or human immunodeficiency virus (HIV), although research in all of these areas is ongoing. The development of a malaria vaccine and an HIV vaccine, in particular, saw promising results in the 2020s. In late 2021, the World Health Organization (WHO) recommended the first malaria vaccine, RTS,S/AS01, for widespread use, primarily for children living in areas with high transmission rates of P. falciparum malaria. In 2023, the WHO also recommended the R21/Matrix-M malaria vaccine for use in countries with high malaria rates. While these vaccines were less effective compared to other vaccines, they help prevent serious illness and death, reducing severe malaria by 30 percent and uncomplicated malaria by 40 percent.

Infectious diseases are not the only possible targets of vaccines. Some researchers are investigating vaccines’ potential for contraception and for treating and preventing diseases such as cocaine addiction, Alzheimer’s disease, and cancer. Others are looking to improve the effectiveness of antigens in stimulating immunity with the use of additives called "adjuvants." In addition, a great deal of research focuses on combining existing vaccines into a reduced total number of injections in the vaccine schedule (the recommended timeline for a given vaccine or vaccines).

Before the invention of vaccines, it was known that people who recovered from certain diseases, such as smallpox, were immune to the disease thereafter. Reportedly, Chinese physicians were the first to try to exploit this phenomenon to prevent disease by drying and grinding up smallpox scabs that were then inhaled by children. In England, contaminating a fresh skin cut, called "variolation," with scabs from smallpox wounds became common in the eighteenth century. Most often, localized skin reactions occurred; serious cases of smallpox were less common. Although only 1 percent of people became seriously sick after variolation, the mortality rate was as high as 50 percent.

English physician Edward Jenner occasionally encountered patients who did not respond with the usual reactions to variolation. According to one story, a milkmaid had told Jenner that she would not get smallpox because she had already had cowpox, a mild disease that causes lesions on the udders of cows and would sometimes infect the hands of milkmaids. Jenner then began to deliberately inoculate people with cowpox in superficial wounds in an attempt to prevent smallpox. The term “vaccination,” from the Latin vacca, or “cow,” was coined in recognition of Jenner’s work.

Because many viral diseases cannot be effectively treated once established, vaccination is the most practical method of controlling them. Controlling viral disease requires that an entire population be immune to it. A phenomenon called herd immunity is established if most of a population is immune. With herd immunity, disease outbreaks are limited to sporadic cases, avoiding epidemic spread of disease. Two centuries after Jenner, smallpox was eliminated worldwide by vaccination. The bifurcated needle, developed in the 1960s and used to scratch the skin and deliver a drop of vaccine, is considered the single most successful medical device ever developed because it helped eliminate the scourge of smallpox.

Principles and Results of Vaccination

A vaccine is a suspension of organisms, or pieces of organisms, delivered to the immune system in various ways. Vaccines offer the immune system a biochemical example of the disease microbe that is used by the body to induce immunity. Both antibody-based, or humoral, immunity and cell-based immunity depend on the formation of immunologic memory. Once vaccinated, immunologic memory is responsible for the rapid neutralizing responses that prevent disease after exposure.

It is now known that Jenner’s inoculations worked because the cowpox virus, which is not a serious pathogen, is closely related to the smallpox virus. The injection by skin scratches provoked a primary immune response against the proteins of the cowpox virus in the recipients, leading to the formation of antibodies and long-term memory cells. Exposure to the smallpox virus and its proteins would then lead to the rapid neutralizing response characteristic of immune people. A vaccinia virus vaccine eventually replaced the cowpox vaccine.

Types of Vaccines and Their Characteristics

There are several basic vaccine types: live-attenuated microbe vaccines, messenger RNA (mRNA) vaccines, inactivated whole-agent vaccines, toxoid vaccines, viral vector vaccines, nucleic acid vaccines, and subunit, recombinant, polysaccharide, and conjugate vaccines.

Live-attenuated microbe vaccines. Attenuated microbe vaccines use living but weakened (attenuated) viruses that cannot cause disease in healthy persons. Live attenuated viruses infect and multiply in the cells of the recipient. Attenuated microbes are usually viral strains derived after mutations accumulated during long-term artificial culture or through genetic manipulation. These microbes no longer cause disease, yet they still are able to cause a low-level infection that generates immunity. Live vaccines more closely mimic an actual infection.

Lifelong immunity is often achieved without booster immunizations, and an effectiveness rate of 95 percent is not unusual. This long-term effectiveness of live viral vaccines probably occurs because the attenuated viruses replicate in the body, increasing the original dose and acting as a series of secondary, or booster, immunizations. Examples of live vaccines include those that protect against smallpox, measles, mumps, and rubella, as well as the oral polio vaccine, no longer available in the United States. Some live-virus vaccines against rotavirus, dengue fever, and other diseases are artificial virus combinations. In development, scientists start with a particular virus’s genetic backbone. Genes from a pathogenic virus are added, and those proteins are produced in infected cells of the vaccine recipient.

The best-known example of a live attenuated bacterial vaccine is the bacillus Calmette-Guérin (BCG) vaccine, which has been used for some time, though with limited efficacy, to combat tuberculosis. It has shown some success as a treatment for superficial or early-stage bladder cancers. To make BCG, tuberculosis bacteria from cows were modified in culture to provide immunity without disease. Modern, genetically modified, live-attenuated vaccines against tuberculosis and typhoid fever are in development. The delivery of the microbes’ proteins is internal and, therefore, distinct from both oral and injectable vaccines.

Attenuated vaccines are not recommended for people whose immune systems are compromised. Because of advances in chemotherapy treatments for cancer, increases in the number of organ transplant recipients taking immunosuppressive drugs, and an increase in the number of people immunocompromised by diseases such as HIV and acquired immunodeficiency syndrome (AIDS), the use of attenuated microbe vaccines should be carefully considered. If available, inactivated vaccines are substituted. A separate danger of such vaccines is the theoretical possibility that the live microbes can mutate back to a virulent form.

Inactivated whole-agent vaccines. Inactivated whole-agent vaccines use microbes that have been killed, usually by formalin or phenol chemical treatment. Inactivated virus vaccines used in humans include those for rabies, influenza, and polio, the latter of which was adopted for use in the United States after 2003. Inactivated bacterial vaccines include those for pneumococcal pneumonia and cholera. Several long-used inactivated vaccines have been replaced by modern, more effective subunit vaccines, including those for pertussis, or whooping cough, and typhoid fever.

Toxoids. Toxoid vaccines are composed of toxins that have been inactivated through chemical or genetic means. As vaccines, they are directed at the toxins produced by a pathogen. The tetanus and diphtheria toxoids have long been part of the standard childhood immunization series. They require a series of injections for full immunity, followed by boosters every ten years. Many older adults have not received boosters, so they are likely to have low levels of protection.

Subunit, recombinant, polysaccharide, and conjugate vaccines.Subunit vaccines use only those molecules or fragments from a microorganism that best stimulates an immune response, referred to as antigenicity. Subunit vaccines that are produced by genetic modification techniques, whereby other microbes are genetically modified to produce the desired antigenic fraction, are called recombinant vaccines. For example, the vaccine against the hepatitis B virus consists of a portion of the viral protein coat that is produced by genetically modified yeast. Vaccines for HPV (Human papillomavirus), like Gardasil 9, are also recombinant vaccines.

Subunit vaccines are inherently safer because they cannot reproduce in the recipient. They also contain little or no extraneous material and, therefore, tend to produce fewer adverse effects. Similarly, it is possible to separate the fractions of a disrupted bacterial cell, retaining the desired antigenic fractions. The acellular vaccines for whooping cough contained in the DTaP (diphtheria, tetanus, and pertussis) vaccine use this approach.

Conjugated vaccines, also referred to as glycoconjugates, have been developed because of the poor immune response of children to vaccines that are based on the capsular polysaccharides surrounding the cell wall of certain bacteria. Polysaccharides are T-independent antigens. This means that a child’s immune system responds to the vaccine through their B cells (lymphocytes) only. Immunologic memory depends on the contributions of T cells. Therefore, polysaccharides do not stimulate immunity until the age of fifteen to twenty-four months. In glycoconjugate technology, polysaccharides are chemically bonded to proteins such as diphtheria or tetanus toxoid. The protein recruits T cells to the vicinity where the polysaccharides and B cells interact. The B cells receive the chemical signal necessary to form immunologic memory from the T cells. This approach has led to the very successful vaccines for Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis that give significant protection, even at two months of age.

Nucleic acid vaccines. Nucleic acid vaccines, or DNA vaccines, use viral genetic sequence-based technology. The injection of plasmids, or small circular DNA (deoxyribonucleic acid) molecules, into muscle results in muscle tissue production of the protein encoded in the DNA. These proteins stimulate an immune response. While the protein is stable enough to stimulate an immune response, the DNA is degraded rapidly, so the supply of protein is not renewed. RNA (ribonucleic acid), which could be made to replicate in the recipient, might be a more effective vaccine.

Viral vector vaccines. Viral vector vaccines use a vector (a harmless virus) to deliver genetic material into the body that contains instructions for cells to produce a specific antigen that creates an immune response that attacks a specific pathogen. Some vaccines developed for COVID-19, measles, and the Ebola virus vaccine are all viral vector vaccines.

Vaccine Safety

Variolation, the first attempt to provide immunity to smallpox, sometimes caused the disease it was intended to prevent. At that time, however, the risk was considered worthwhile. The orally delivered live attenuated polio vaccine was effective at reducing polio in the face of an epidemic. On rare occasions, it caused a mild form of the disease. Therefore, the lower-risk inactivated poliovirus vaccine was adopted in the developed world when epidemics were rarer.

In 1999, a rotavirus vaccine for children was withdrawn from the market because several recipients developed a life-threatening intestinal obstruction called "intussusception." Eventually, it was determined that the vaccine was not the cause, and some experts suggested that it be reintroduced in developing countries where the incidence of rotavirus is high. New, safer versions of the vaccine were introduced in 2006 and 2008.

Public reaction to such risks has changed. Most parents have never seen a case of polio or measles and, therefore, tend to view the risk of these diseases as remote. Rumored reports of harmful effects often lead people to avoid certain vaccines. In particular, a contrived connection between the MMR (measles, mumps, rubella) vaccine and autism has received widespread publicity. Autism is a complex and often poorly understood neurodevelopmental condition that causes a child, in part, to withdraw to varying degrees from everyday reality, namely other persons. Because autism is usually diagnosed at the age of eighteen to thirty months, the age range in which vaccination is common in the United States and Europe, some persons claimed a cause-and-effect connection between the vaccines and autism. Medically, however, experts overwhelmingly agree that autism is a condition with a major genetic component that begins before birth. Moreover, the first study to propose a causal link between the MMR vaccine and autism, published in 1998 by former surgeon Andrew Wakefield, was later found to be fraudulent and officially retracted. The large increase in autism diagnoses is caused primarily by the greatly expanded definition of autism spectrum disorders and not by the adoption of certain vaccines. All testimony to the contrary has been discredited.

Thimerosal is a mercury-containing organic compound. Beginning in the 1930s, it was widely used as a preservative in multi-dose vaccines to help prevent fungal and bacterial contamination. Concerns about thimerosal were raised in the 1990s due to mercury's potential for neurotoxicity and the increased number of thimerosal-containing vaccines added to the immunization schedule. Because of these concerns, the US Food and Drug Administration (FDA) worked with vaccine manufacturers to gradually eliminate thimerosal from vaccines. In the US, thimerosal was removed from all childhood vaccines in 2001, and the only adult vaccine that contained the preservative in the 2020s was the multi-dose inactivated influenza vaccine. Though thimerosal was removed as a precautionary measure, no scientific correlation has been established linking the chemical and adverse health impacts.

Challenges of Vaccination

The economics of vaccination. Although interest in vaccine development declined with the introduction of antibiotics, it intensified in the late twentieth and early twenty-first centuries. Fear of litigation had contributed to decreased development of new vaccines in the United States and in Europe, but the passage of the National Childhood Vaccine Injury Act in 1986, which limited the liability of vaccine manufacturers in the United States, helped reverse this trend. Even so, to the pharmaceutical industry, vaccines are inherently less attractive economically than drug treatments that last for extended periods of time.

Cultivation of vaccine microbes and antigens. Vaccines can be developed only by growing the pathogen in large quantities. The early successful viral vaccines were developed by animal cultivation. The vaccinia virus for smallpox was grown on the shaved bellies of calves, for example. However, some viruses, such as polio, measles, and mumps, will not grow in anything except living human cells. The introduction of vaccines against these and other such viral diseases awaited the development of cell culture techniques. Cell cultures from human sources enabled the growth of these viruses on a large scale.

A valuable biological resource for the cultivation of viruses is the chick embryo. Viruses for several vaccines, including influenza, are grown in the various anatomic compartments of the egg. However, recombinant vaccines and DNA vaccines do not need a cell or animal host to grow the vaccine’s microbe. This avoids a major problem with certain viruses that have not been grown in cell culture, such as hepatitis B. (The first hepatitis B vaccine used viral antigens extracted from the blood of chronically infected humans because no other source was available.)

Distribution and delivery of vaccines. Diarrheal diseases are a major cause of mortality for infants in developing countries, where costs and distribution of vaccines also pose special problems. For example, a vaccine that must be refrigerated would be nearly useless in countries that lack reliable electrical service. As an alternative, edible, plant-derived vaccines of several types are undergoing clinical trials.

Impact

Infectious diseases place a heavy burden on public health in many parts of the world. The cost of human suffering, social hardship, and economic cost is huge. Consequently, preventing and combating these diseases are keys to the economic development of many underdeveloped regions.

A number of diseases are vaccine-preventable. The introduction of immunization has been one of the greatest and most cost-effective interventions in human health. The health impact of vaccination programs is tremendous, perhaps surpassed in significance only by measures to prevent poverty and to introduce sanitation systems for clean water.

Vaccines continue to evolve, and scientists develop new ways to immunize the human body against dangerous pathogens. Research involving recombinant vector vaccines (platform-based vaccines) and DNA vaccines continues to increase. Following the development of the COVID-19 vaccine, mRNA vaccine development accelerated, including the introduction of self-amplifying RNA (saRNA) and circular RNA (circRNA) technologies.

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