14.4: Vaccines - Biology

14.4: Vaccines - Biology

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Learning Objectives

  • Compare the various kinds of artificial immunity
  • Differentiate between variolation and vaccination
  • Describe different types of vaccines and explain their respective advantages and disadvantages

For many diseases, prevention is the best form of treatment, and few strategies for disease prevention are as effective as vaccination. Vaccination is a form of artificial immunity. By artificially stimulating the adaptive immune defenses, a vaccine triggers memory cell production similar to that which would occur during a primary response. In so doing, the patient is able to mount a strong secondary response upon exposure to the pathogen—but without having to first suffer through an initial infection. In this section, we will explore several different kinds of artificial immunity along with various types of vaccines and the mechanisms by which they induce artificial immunity.

Classifications of Adaptive Immunity

All forms of adaptive immunity can be described as either active or passive. Active immunity refers to the activation of an individual’s own adaptive immune defenses, whereas passive immunity refers to the transfer of adaptive immune defenses from another individual or animal. Active and passive immunity can be further subdivided based on whether the protection is acquired naturally or artificially.

Natural active immunity is adaptive immunity that develops after natural exposure to a pathogen (Figure (PageIndex{1})). Examples would include the lifelong immunity that develops after recovery from a chickenpox or measles infection (although an acute infection is not always necessary to activate adaptive immunity). The length of time that an individual is protected can vary substantially depending upon the pathogen and antigens involved. For example, activation of adaptive immunity by protein spike structures during an intracellular viral infection can activate lifelong immunity, whereas activation by carbohydrate capsule antigens during an extracellular bacterial infection may activate shorter-term immunity.

Natural passive immunity involves the natural passage of antibodies from a mother to her child before and after birth. IgG is the only antibody class that can cross the placenta from mother’s blood to the fetal blood supply. Placental transfer of IgG is an important passive immune defense for the infant, lasting up to six months after birth. Secretory IgA can also be transferred from mother to infant through breast milk.

Artificial passive immunity refers to the transfer of antibodies produced by a donor (human or animal) to another individual. This transfer of antibodies may be done as a prophylactic measure (i.e., to prevent disease after exposure to a pathogen) or as a strategy for treating an active infection. For example, artificial passive immunity is commonly used for post-exposure prophylaxis against rabies, hepatitis A, hepatitis B, and chickenpox (in high risk individuals). Active infections treated by artificial passive immunity include cytomegalovirus infections in immunocompromised patients and Ebola virus infections. In 1995, eight patients in the Democratic Republic of the Congo with active Ebola infections were treated with blood transfusions from patients who were recovering from Ebola. Only one of the eight patients died (a 12.5% mortality rate), which was much lower than the expected 80% mortality rate for Ebola in untreated patients.1 Artificial passive immunity is also used for the treatment of diseases caused by bacterial toxins, including tetanus, botulism, and diphtheria.

Artificial active immunity is the foundation for vaccination. It involves the activation of adaptive immunity through the deliberate exposure of an individual to weakened or inactivated pathogens, or preparations consisting of key pathogen antigens.

Exercise (PageIndex{1})

  1. What is the difference between active and passive immunity?
  2. What kind of immunity is conferred by a vaccine?

Herd Immunity

The four kinds of immunity just described result from an individual’s adaptive immune system. For any given disease, an individual may be considered immune or susceptible depending on his or her ability to mount an effective immune response upon exposure. Thus, any given population is likely to have some individuals who are immune and other individuals who are susceptible. If a population has very few susceptible individuals, even those susceptible individuals will be protected by a phenomenon called herd immunity. Herd immunity has nothing to do with an individual’s ability to mount an effective immune response; rather, it occurs because there are too few susceptible individuals in a population for the disease to spread effectively.

Vaccination programs create herd immunity by greatly reducing the number of susceptible individuals in a population. Even if some individuals in the population are not vaccinated, as long as a certain percentage is immune (either naturally or artificially), the few susceptible individuals are unlikely to be exposed to the pathogen. However, because new individuals are constantly entering populations (for example, through birth or relocation), vaccination programs are necessary to maintain herd immunity.

Vaccination: Obligation or Choice

A growing number of parents are choosing not to vaccinate their children. They are dubbed “antivaxxers,” and the majority of them believe that vaccines are a cause of autism (or other disease conditions), a link that has now been thoroughly disproven. Others object to vaccines on religious or moral grounds (e.g., the argument that Gardasil vaccination against HPV may promote sexual promiscuity), on personal ethical grounds (e.g., a conscientious objection to any medical intervention), or on political grounds (e.g., the notion that mandatory vaccinations are a violation of individual liberties).2

It is believed that this growing number of unvaccinated individuals has led to new outbreaks of whooping cough and measles. We would expect that herd immunity would protect those unvaccinated in our population, but herd immunity can only be maintained if enough individuals are being vaccinated.

Vaccination is clearly beneficial for public health. But from the individual parent’s perspective the view can be murkier. Vaccines, like all medical interventions, have associated risks, and while the risks of vaccination may be extremely low compared to the risks of infection, parents may not always understand or accept the consensus of the medical community. Do such parents have a right to withhold vaccination from their children? Should they be allowed to put their children—and society at large—at risk?

Many governments insist on childhood vaccinations as a condition for entering public school, but it has become easy in most states to opt out of the requirement or to keep children out of the public system. Since the 1970s, West Virginia and Mississippi have had in place a stringent requirement for childhood vaccination, without exceptions, and neither state has had a case of measles since the early 1990s. California lawmakers recently passed a similar law in response to a measles outbreak in 2015, making it much more difficult for parents to opt out of vaccines if their children are attending public schools. Given this track record and renewed legislative efforts, should other states adopt similarly strict requirements?

What role should health-care providers play in promoting or enforcing universal vaccination? Studies have shown that many parents’ minds can be changed in response to information delivered by health-care workers, but is it the place of health-care workers to try to persuade parents to have their children vaccinated? Some health-care providers are understandably reluctant to treat unvaccinated patients. Do they have the right to refuse service to patients who decline vaccines? Do insurance companies have the right to deny coverage to antivaxxers? These are all ethical questions that policymakers may be forced to address as more parents skirt vaccination norms.

Variolation and Vaccination

Thousands of years ago, it was first recognized that individuals who survived a smallpox infection were immune to subsequent infections. The practice of inoculating individuals to actively protect them from smallpox appears to have originated in the 10th century in China, when the practice of variolation was described (Figure (PageIndex{2})). Variolation refers to the deliberate inoculation of individuals with infectious material from scabs or pustules of smallpox victims. Infectious materials were either injected into the skin or introduced through the nasal route. The infection that developed was usually milder than naturally acquired smallpox, and recovery from the milder infection provided protection against the more serious disease.

Although the majority of individuals treated by variolation developed only mild infections, the practice was not without risks. More serious and sometimes fatal infections did occur, and because smallpox was contagious, infections resulting from variolation could lead to epidemics. Even so, the practice of variolation for smallpox prevention spread to other regions, including India, Africa, and Europe.

Although variolation had been practiced for centuries, the English physician Edward Jenner (1749–1823) is generally credited with developing the modern process of vaccination. Jenner observed that milkmaids who developed cowpox, a disease similar to smallpox but milder, were immune to the more serious smallpox. This led Jenner to hypothesize that exposure to a less virulent pathogen could provide immune protection against a more virulent pathogen, providing a safer alternative to variolation. In 1796, Jenner tested his hypothesis by obtaining infectious samples from a milkmaid’s active cowpox lesion and injecting the materials into a young boy (Figure (PageIndex{3})). The boy developed a mild infection that included a low-grade fever, discomfort in his axillae (armpit) and loss of appetite. When the boy was later infected with infectious samples from smallpox lesions, he did not contract smallpox.3 This new approach was termed vaccination, a name deriving from the use of cowpox (Latin vacca meaning “cow”) to protect against smallpox. Today, we know that Jenner’s vaccine worked because the cowpox virus is genetically and antigenically related to the Variola viruses that caused smallpox. Exposure to cowpox antigens resulted in a primary response and the production of memory cells that identical or related epitopes of Variola virus upon a later exposure to smallpox.

The success of Jenner’s smallpox vaccination led other scientists to develop vaccines for other diseases. Perhaps the most notable was Louis Pasteur, who developed vaccines for rabies, cholera, and anthrax. During the 20th and 21stcenturies, effective vaccines were developed to prevent a wide range of diseases caused by viruses (e.g., chickenpox and shingles, hepatitis, measles, mumps, polio, and yellow fever) and bacteria (e.g., diphtheria, pneumococcal pneumonia, tetanus, and whooping cough,).

Exercise (PageIndex{2})

  1. What is the difference between variolation and vaccination for smallpox?
  2. Explain why vaccination is less risky than variolation.

Classes of Vaccines

For a vaccine to provide protection against a disease, it must expose an individual to pathogen-specific antigens that will stimulate a protective adaptive immune response. By its very nature, this entails some risk. As with any pharmaceutical drug, vaccines have the potential to cause adverse effects. However, the ideal vaccine causes no severe adverse effects and poses no risk of contracting the disease that it is intended to prevent. Various types of vaccines have been developed with these goals in mind. These different classes of vaccines are described in the next section and summarized in Table (PageIndex{1}).

Live Attenuated Vaccines

Live attenuated vaccines expose an individual to a weakened strain of a pathogen with the goal of establishing a subclinical infection that will activate the adaptive immune defenses. Pathogens are attenuated to decrease their virulence using methods such as genetic manipulation (to eliminate key virulence factors) or long-term culturing in an unnatural host or environment (to promote mutations and decrease virulence).

By establishing an active infection, live attenuated vaccines stimulate a more comprehensive immune response than some other types of vaccines. Live attenuated vaccines activate both cellular and humoral immunity and stimulate the development of memory for long-lasting immunity. In some cases, vaccination of one individual with a live attenuated pathogen can even lead to natural transmission of the attenuated pathogen to other individuals. This can cause the other individuals to also develop an active, subclinical infection that activates their adaptive immune defenses.

Disadvantages associated with live attenuated vaccines include the challenges associated with long-term storage and transport as well as the potential for a patient to develop signs and symptoms of disease during the active infection (particularly in immunocompromised patients). There is also a risk of the attenuated pathogen reverting back to full virulence. Table (PageIndex{1}) lists examples live attenuated vaccines.

Inactivated Vaccines

Inactivated vaccines contain whole pathogens that have been killed or inactivated with heat, chemicals, or radiation. For inactivated vaccines to be effective, the inactivation process must not affect the structure of key antigens on the pathogen.

Because the pathogen is killed or inactive, inactivated vaccines do not produce an active infection, and the resulting immune response is weaker and less comprehensive than that provoked by a live attenuated vaccine. Typically the response involves only humoral immunity, and the pathogen cannot be transmitted to other individuals. In addition, inactivated vaccines usually require higher doses and multiple boosters, possibly causing inflammatory reactions at the site of injection.

Despite these disadvantages, inactivated vaccines do have the advantages of long-term storage stability and ease of transport. Also, there is no risk of causing severe active infections. However, inactivated vaccines are not without their side effects. Table (PageIndex{1}) lists examples of inactivated vaccines.

Subunit Vaccines

Whereas live attenuated and inactive vaccines expose an individual to a weakened or dead pathogen, subunit vaccinesonly expose the patient to the key antigens of a pathogen—not whole cells or viruses. Subunit vaccines can be produced either by chemically degrading a pathogen and isolating its key antigens or by producing the antigens through genetic engineering. Because these vaccines contain only the essential antigens of a pathogen, the risk of side effects is relatively low. Table (PageIndex{1}) lists examples of subunit vaccines.

Toxoid Vaccines

Like subunit vaccines, toxoid vaccines do not introduce a whole pathogen to the patient; they contain inactivated bacterial toxins, called toxoids. Toxoid vaccines are used to prevent diseases in which bacterial toxins play an important role in pathogenesis. These vaccines activate humoral immunity that neutralizes the toxins. Table (PageIndex{1})lists examples of toxoid vaccines.

Conjugate Vaccines

A conjugate vaccine is a type of subunit vaccine that consists of a protein conjugated to a capsule polysaccharide. Conjugate vaccines have been developed to enhance the efficacy of subunit vaccines against pathogens that have protective polysaccharide capsules that help them evade phagocytosis, causing invasive infections that can lead to meningitis and other serious conditions. The subunit vaccines against these pathogens introduce T-independent capsular polysaccharide antigens that result in the production of antibodies that can opsonize the capsule and thus combat the infection; however, children under the age of two years do not respond effectively to these vaccines. Children do respond effectively when vaccinated with the conjugate vaccine, in which a protein with T-dependent antigens is conjugated to the capsule polysaccharide. The conjugated protein-polysaccharide antigen stimulates production of antibodies against both the protein and the capsule polysaccharide. Table (PageIndex{1}) lists examples of conjugate vaccines.

Table (PageIndex{1}): Classes of Vaccines

Live attenuatedWeakened strain of whole pathogenCellular and humoral immunityDifficult to store and transportChickenpox, German measles, measles, mumps, tuberculosis, typhoid fever, yellow fever
Long-lasting immunityRisk of infection in immunocompromised patients
Transmission to contactsRisk of reversion
InactivatedWhole pathogen killed or inactivated with heat, chemicals, or radiationEase of storage and transportWeaker immunity (humoral only)Cholera, hepatitis A, influenza, plague, rabies
No risk of severe active infectionHigher doses and more boosters required
SubunitImmunogenic antigensLower risk of side effectsLimited longevityAnthrax, hepatitis B, influenza, meningitis, papillomavirus, pneumococcal pneumonia, whooping cough
Multiple doses required
No protection against antigenic variation
ToxoidInactivated bacterial toxinHumoral immunity to neutralize toxinDoes not prevent infectionBotulism, diphtheria, pertussis, tetanus
ConjugateCapsule polysaccharide conjugated to proteinT-dependent response to capsuleCostly to produce


(Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitides)

No protection against antigenic variation
Better response in young childrenMay interfere with other vaccines

Exercise (PageIndex{3})

  1. What is the risk associated with a live attenuated vaccine?
  2. Why is a conjugated vaccine necessary in some cases?

DNA Vaccines

DNA vaccines represent a relatively new and promising approach to vaccination. A DNA vaccine is produced by incorporating genes for antigens into a recombinant plasmid vaccine. Introduction of the DNA vaccine into a patient leads to uptake of the recombinant plasmid by some of the patient’s cells, followed by transcription and translation of antigens and presentation of these antigens with MHC I to activate adaptive immunity. This results in the stimulation of both humoral and cellular immunity without the risk of active disease associated with live attenuated vaccines.

Although most DNA vaccines for humans are still in development, it is likely that they will become more prevalent in the near future as researchers are working on engineering DNA vaccines that will activate adaptive immunity against several different pathogens at once. First-generation DNA vaccines tested in the 1990s looked promising in animal models but were disappointing when tested in human subjects. Poor cellular uptake of the DNA plasmids was one of the major problems impacting their efficacy. Trials of second-generation DNA vaccines have been more promising thanks to new techniques for enhancing cellular uptake and optimizing antigens. DNA vaccines for various cancers and viral pathogens such as HIV, HPV, and hepatitis B and C are currently in development.

Some DNA vaccines are already in use. In 2005, a DNA vaccine against West Nile virus was approved for use in horses in the United States. Canada has also approved a DNA vaccine to protect fish from infectious hematopoietic necrosis virus.4 A DNA vaccine against Japanese encephalitis virus was approved for use in humans in 2010 in Australia.

Clinical Focus: Resolution

Based on Olivia’s symptoms, her physician made a preliminary diagnosis of bacterial meningitis without waiting for positive identification from the blood and CSF samples sent to the lab. Olivia was admitted to the hospital and treated with intravenous broad-spectrum antibiotics and rehydration therapy. Over the next several days, her condition began to improve, and new blood samples and lumbar puncture samples showed an absence of microbes in the blood and CSF with levels of white blood cells returning to normal. During this time, the lab produced a positive identification of Neisseria meningitidis, the causative agent of meningococcal meningitis, in her original CSF sample.

N. meningitidis produces a polysaccharide capsule that serves as a virulence factor. N. meningitidis tends to affect infants after they begin to lose the natural passive immunity provided by maternal antibodies. At one year of age, Olivia’s maternal IgG antibodies would have disappeared, and she would not have developed memory cells capable of recognizing antigens associated with the polysaccharide capsule of the N. meningitidis. As a result, her adaptive immune system was unable to produce protective antibodies to combat the infection, and without antibiotics she may not have survived. Olivia’s infection likely would have been avoided altogether had she been vaccinated. A conjugate vaccine to prevent meningococcal meningitis is available and approved for infants as young as two months of age. However, current vaccination schedules in the United States recommend that the vaccine be administered at age 11–12 with a booster at age 16.

In countries with developed public health systems, many vaccines are routinely administered to children and adults. Vaccine schedules are changed periodically, based on new information and research results gathered by public health agencies. In the United States, the CDC publishes schedules and other updated information about vaccines.

Key Concepts and Summary

  • Adaptive immunity can be divided into four distinct classifications: natural active immunity, natural passive immunity, artificial passive immunity, and artificial active immunity.
  • Artificial active immunity is the foundation for vaccination and vaccine development. Vaccination programs not only confer artificial immunity on individuals, but also foster herd immunity in populations.
  • Variolation against smallpox originated in the 10th century in China, but the procedure was risky because it could cause the disease it was intended to prevent. Modern vaccination was developed by Edward Jenner, who developed the practice of inoculating patients with infectious materials from cowpox lesions to prevent smallpox.
  • Live attenuated vaccines and inactivated vaccines contain whole pathogens that are weak, killed, or inactivated. Subunit vaccines, toxoid vaccines, and conjugate vaccines contain acellular components with antigens that stimulate an immune response.


  1. K. Mupapa, M. Massamba, K. Kibadi, K. Kivula, A. Bwaka, M. Kipasa, R. Colebunders, J. J. Muyembe-Tamfum. “Treatment of Ebola Hemorrhagic Fever with Blood Transfusions from Convalescent Patients.” Journal of Infectious Diseases 179 Suppl. (1999): S18–S23.
  2. Elizabeth Yale. “Why Anti-Vaccination Movements Can Never Be Tamed.” Religion & Politics, July 22, 2014.
  3. N. Willis. “Edward Jenner and the Eradication of Smallpox.” Scottish Medical Journal 42 (1997): 118–121.
  4. M. Alonso and J. C. Leong. “Licensed DNA Vaccines Against Infectious Hematopoietic Necrosis Virus (IHNV).” Recent Patents on DNA & Gene Sequences (Discontinued) 7 no. 1 (2013): 62–65, issn 1872-2156/2212-3431. doi 10.2174/1872215611307010009.
  5. S.B. Halstead and S. Thomas. “New Japanese Encephalitis Vaccines: Alternatives to Production in Mouse Brain.” Expert Review of Vaccines 10 no. 3 (2011): 355–64.

Emergency use listing

The WHO Emergency Use Listing Procedure (EUL) is a risk-based procedure for assessing and listing unlicensed vaccines, therapeutics and in vitro diagnostics with the ultimate aim of expediting the availability of these products to people affected by a public health emergency. This will assist interested UN procurement agencies and Member States in determining the acceptability of using specific products, based on an essential set of available quality, safety, and efficacy and performance data.

The procedure is a key tool for companies wishing to submit their products for use during health emergencies.

Eligibility of candidate products

The EUL concerns three product streams (vaccines, therapeutics and in vitro diagnostics), each of which has specific requirements for products to be eligible for evaluation under the EUL procedure.

The following criteria must be met:

  • The disease for which the product is intended is serious or immediately life threatening, has the potential of causing an outbreak, epidemic or pandemic and it is reasonable to consider the product for an EUL assessment, e.g., there are no licensed products for the indication or for a critical subpopulation (e.g., children)
  • Existing products have not been successful in eradicating the disease or preventing outbreaks (in the case of vaccines and medicines)
  • The product is manufactured in compliance with current Good Manufacturing Practices (GMP) in the case of medicines and vaccines and under a functional Quality Management System (QMS) in the case of IVDs and
  • The applicant undertakes to complete the development of the product (validation and verification of the product in the case of IVDs) and apply for WHO prequalification once the product is licensed.

Information on EUL vaccines

More information can be found here.

The contact email for Vaccines EUL submissions and more information is [email protected]

Information on EUL in vitro diagnostics

Instructions for manufacturers detailing the technical specifications for the documentary evidence can be found here.

The contact email for IVDs EUL submissions and more information is [email protected]


Two of the Coronavirus Disease 2019 (COVID-19) vaccines currently approved in the United States require 2 doses, administered 3 to 4 weeks apart. Constraints in vaccine supply and distribution capacity, together with a deadly wave of COVID-19 from November 2020 to January 2021 and the emergence of highly contagious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants, sparked a policy debate on whether to vaccinate more individuals with the first dose of available vaccines and delay the second dose or to continue with the recommended 2-dose series as tested in clinical trials. We developed an agent-based model of COVID-19 transmission to compare the impact of these 2 vaccination strategies, while varying the temporal waning of vaccine efficacy following the first dose and the level of preexisting immunity in the population. Our results show that for Moderna vaccines, a delay of at least 9 weeks could maximize vaccination program effectiveness and avert at least an additional 17.3 (95% credible interval [CrI]: 7.8–29.7) infections, 0.69 (95% CrI: 0.52–0.97) hospitalizations, and 0.34 (95% CrI: 0.25–0.44) deaths per 10,000 population compared to the recommended 4-week interval between the 2 doses. Pfizer-BioNTech vaccines also averted an additional 0.60 (95% CrI: 0.37–0.89) hospitalizations and 0.32 (95% CrI: 0.23–0.45) deaths per 10,000 population in a 9-week delayed second dose (DSD) strategy compared to the 3-week recommended schedule between doses. However, there was no clear advantage of delaying the second dose with Pfizer-BioNTech vaccines in reducing infections, unless the efficacy of the first dose did not wane over time. Our findings underscore the importance of quantifying the characteristics and durability of vaccine-induced protection after the first dose in order to determine the optimal time interval between the 2 doses.

Citation: Moghadas SM, Vilches TN, Zhang K, Nourbakhsh S, Sah P, Fitzpatrick MC, et al. (2021) Evaluation of COVID-19 vaccination strategies with a delayed second dose. PLoS Biol 19(4): e3001211.

Academic Editor: Andrew Fraser Read, The Pennsylvania State University, UNITED STATES

Received: January 28, 2021 Accepted: March 29, 2021 Published: April 21, 2021

Copyright: © 2021 Moghadas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Computational model and data/parameters are available at: All raw data are available at:

Funding: The authors received funding from the following sources: SMM: Canadian Institutes of Health Research [OV4 – 170643, COVID-19 Rapid Research] TNV: São Paulo Research Foundation [18/24811-1] APG, MCF: the National Institutes of Health [1RO1AI151176-01 1K01AI141576-01] APG: the National Science Foundation [RAPID 2027755 CCF-1918784]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors declare that they have no competing interests.

Abbreviations: COVID-19, Coronavirus Disease 2019 Crl, credible interval DSD, delayed second dose FDA, Food and Drug Administration ICU, intensive care unit SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2

14.4 Animal sex, from fish to birds

Most fish have external fertilization, but many have highly ritualized courtship routines that they use to choose a mate. The male will often perform courtship demonstrations of dancing, nest building or territory defense. (See examples of these with puffer fish, clown fish, and trumpet fish.) The male will follow the female, and once she deposits eggs on a surface, he will follow and deposit milt (the fish semen that contains sperm) over top.

A few fish (like guppies) have internal fertilization, in which the male inserts a specialized tubular fin into the female reproductive opening and deposits sperm into her reproductive tract.

Some fish are mouthbrooders, meaning that one fish puts the eggs in its mouth for incubation. Many cichlids are maternal mouth brooders. For these fish, the female lays the eggs and then picks them up in her mouth. Male fish will then encourage the female fish to open her mouth and will fertilize the eggs while in her mouth. For paternal mouth-brooding fish, the male puts the eggs in his mouth to incubate after he has fertilized them externally. Recall the discussion of anal-fin egg mimicry in Chapter 4…cichlid fish are fascinating!


Like fish, many amphibians have external fertilization. Many frogs and toads, for example, have a courting ritual in which the male frog rides on the female’s back and places specialized digits (essentially frog thumbs) on either side of the female in specialized, so-called nuptial pads. This grip helps keep the male frog from falling off as the female hops or swims around. The female eventually deposits her eggs and the male is in an ideal position to fertilize them.

Figure 14.4 Frog thumbs

A few salamanders perform external fertilization similar to that of frogs and toads, however most salamanders have internal fertilization. Male salamanders do not have penises to deposit sperm inside the female. Rather, they deposit an encased capsule of sperm and nutrients, a spermatophore, on the ground as part of a mating ritual. A female can pick up the spermatophore with her cloaca (a combined urinary and genital opening) and will use these sperm to fertilize her eggs internally. Most salamanders will then lay the fertilized eggs, however in a few species (such as the fire salamander) the eggs hatch inside the female and the female gives birth to larval salamanders.


Reptiles (e.g., lizards, turtles, snakes, and crocodiles) have internal fertilization. Reptiles have a great diversity of penises some have a penis that is branched at the end (each end is called a hemipenis reptiles only use one at a time), and some tortoises have umbrella-shaped penises. Some reptiles give birth to live young (called viviparity) and some lay eggs.


Most birds do not have penises, but achieve internal fertilization via cloacal contact (or “cloaca kiss”). In these birds, males and females contact their cloacas together, typically briefly, and transfer sperm to the female. Interestingly, water fowl such as ducks and geese have penises and use them for internal fertilization. Why would some birds use penises for fertilization, while others do not?

  1. Photo by Christophe Meneboeuf &crarr


The three letters “DNA” have now become synonymous with crime solving and genetic testing. DNA can be retrieved from hair, blood, or saliva. Each person’s DNA is unique, and it is possible to detect differences between individuals within a species on the basis of these unique features.

DNA analysis has many practical applications beyond forensics. In humans, DNA testing is applied to numerous uses: determining paternity, tracing genealogy, identifying pathogens, archeological research, tracing disease outbreaks, and studying human migration patterns. In the medical field, DNA is used in diagnostics, new vaccine development, and cancer therapy. It is now possible to determine predisposition to diseases by looking at genes.

Each human cell has 23 pairs of chromosomes: one set of chromosomes is inherited from the mother and the other set is inherited from the father. There is also a mitochondrial genome, inherited exclusively from the mother, which can be involved in inherited genetic disorders. On each chromosome, there are thousands of genes that are responsible for determining the genotype and phenotype of the individual. A gene is defined as a sequence of DNA that codes for a functional product. The human haploid genome contains 3 billion base pairs and has between 20,000 and 25,000 functional genes.

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    Immunotherapy includes the use of certain components of the immune system (antibodies, cells, cytokines, etc.) for the treatment of various cancers and autoimmune diseases and the manipulation of the immune system through vaccines for the prevention and treatment of infectious and allergic diseases (Fig. 1).

    Examples of immunotherapy, including the use of vaccines, monoclonal antibodies, fusion proteins, bacteria, oncolytic viruses, cytokines, and different types of cellular immunotherapy: chimeric antigen receptor (CAR) T cells, dendritic and mesenchymal cells, tumor-infiltrating lymphocytes, regulatory (Treg) and gamma/delta (Tγ/δ) T cells, lymphocyte activated killer (LAK) and natural killer (NK) cells

    Immunotherapy using microorganisms or their components in vaccines was first practiced centuries ago soluble substances such as poly- and monoclonal antibodies, as well as cytokines, have been used for many years, but recently, cellular immunotherapy has emerged in clinical practice. Although immunotherapy can be used for many diseases (infections, autoimmune diseases, macular degeneration, allergic diseases, etc.), it is being used most expansively in the cancer field. The main goal is to destroy the tumor, either directly or indirectly (by enhancing the patient’s immune system), while offering greater specificity and fewer side effects than conferred by conventional therapies.

    Pathogens and vaccines for infectious diseases

    Immunotherapy associated with pathogens was first linked to the prevention of infectious diseases, starting from variolization (in the X century), followed by Edward Jenner’s vaccination against smallpox (in the XVIII century) and subsequently many other preventive vaccines for infectious diseases. The great advances in the knowledge about infectious diseases took place in the nineteenth century, but the XX and XXI centuries are clearly the vaccination centuries, as many new successful vaccines (with attenuated or dead pathogens, subunits, recombinant proteins, carbohydrates or DNA) introduced against a variety of pathogens. Currently, vaccines are among the factors that, together with hygiene, antibiotics and surgery, save the most lives 181 . Vaccination enabled the eradication of smallpox infection worldwide in 1980, and we are quite close to eradicating polio 182 . However, new and better vaccines are urgently needed e.g., a vaccine against the new coronavirus 2019, SARS-Cov-2 prevalent pathogens, such as human immunodeficiency virus (HIV) parasites, such as Plasmodium spp., which produce malaria and bacteria, such as Mycobacterium tuberculosis. However, anti-vaccine groups in more affluent countries are putting society at risk for a return of the serious illnesses that had almost been forgotten, such as diphtheria and tetanus 183 , with an increase in measles in unvaccinated people at epidemic levels, thus negating many of the advances made over many years.

    Therapy with microorganisms


    Whole pathogens or their products can also be used in human therapy for some types of cancer. At the end of the XIX century, the father of immunotherapy, Dr. Coley, popularized the use of extracts from cultures of Streptococcus pyogenes and Serratia marcescens 184 (called Coley’s toxin) for the treatment of patients with sarcoma, lymphoma, testis cancer, etc., but because of variable results and, indeed, cases of death, these treatments were discontinued. Later, because of the research on cancer performed by Dr. Lloyd J. Old with Mycobacteria, bacillus Calmette-Guérin (BCG) was approved by the American Food and Drug Administration (FDA) in 1976 for use in a therapeutic procedure for bladder cancer —a treatment that is still in use today 185,186 .

    More recently, and with the increased knowledge of the human microbiome, the use of microorganisms in therapy has seen a resurgence. Some intestinal infections, such as those produced by Clostridium difficile, can be cured with the transfer of intestinal bacteria from healthy people (feces transplantation) 187 . Numerous other attempts to use microorganisms to cure inflammatory illnesses (Crohn’s disease, ulcerative colitis, etc.) have met with limited success 188 , which indicates that this type of therapy is much more complex than initially anticipated. As a consequence, many more studies are required to ensure that this approach can be used for curative immunotherapy. Researchers are also working on genetically modified or artificial bacteria (e.g., based on Salmonella enterica, Listeria monocytogenes or Lactobacillus lactis), but only limited effects have been observed to date 189 .

    Oncolytic viruses (OVs)

    Although the use of bacteria in antitumoral therapy has been largely restricted, the use of therapeutic viruses is increasing. Virus-based therapy was introduced in the 1990s with the use of adenovirus, but only in recent years has it been used in practice in the clinic. Oncologic viruses 190 have the capacity to attack tumor cells in a preferential manner and induce immunogenic cell death (ICD) and host antitumor immunity (Fig. 2).

    Oncolytic viruses replicate inside tumor cells, which causes cell lysis. In addition, the expression of viral antigens induces an antiviral immune response that helps destroy tumor cells

    The first virus approved for use in therapy was a recombinant oncolytic adenovirus named H101, which was licensed in 2005 by the China Food and Drug Administration (CFDA) for treating head and neck carcinoma in combination with chemotherapy 191 . Ten years later, the oncolytic attenuated-modified virus herpes simplex I-talimogene laherparepvec (T-VEC, Imlygic®) was approved by both European (EMEA) and American (FDA) agencies for the treatment of melanoma 192 . The virus is modified by the insertion of human GM-CSF and deletion of the ICP47 gene. Since the approval of T-VEC, a new era has dawned on the use of OVs in cancer therapy 193,194 .

    Currently, oncolytic viruses from the Adenoviridae, Herpesviridae, Picornaviridae, Reoviridae and Poxviridae families are in different phases of clinical studies for several types of tumors 194,195 . For example, reovirus against brain tumors (alone or combined with other therapies) 196 or Maraba virus against triple-negative breast tumors 197,198 offer some hope to patients with these types of cancer.

    Viral sequences can be modified by genetic engineering techniques, thus making the virus more prone to infect some cells and enhancing viral infiltration and tumor tropism. Combinations with other components (immunomodulators, drugs, and cytokines) are also being explored to suppress antiviral immunity and enhance antitumoral cytotoxicity 199 .

    Other vaccines

    Vaccines for cancer prevention

    It is clear that certain viruses and bacteria play roles in cancer development. Viruses such as genital herpes, hepatitis B, Epstein Barr or human papilloma and bacteria such as Helicobacter pylori have been associated with cancers of the uterus and liver, in Burkitt’s lymphoma, and oral/genital and stomach cancers, respectively 200 . Therefore, immunization against these pathogens offer protection not only from infection but also from cancer.

    Therapeutic vaccines

    Once an illness has developed, the intention of a therapeutic vaccine is to eliminate or decrease its pathology. Thus, vaccines are used for cases of allergies, cancers and autoimmune diseases.

    Allergy (Type 1)

    Allergen-specific immunotherapy (AIT) aims to modulate the immune system against an allergen, thus modifying the natural course of the allergic disease and conferring long-lasting benefits 201 . The basic AIT involves the introduction of repeated doses of allergen (either injectable or sublingual allergen extract tablets) and often in escalating doses in a controlled manner, followed by a maintenance phase. In cases for which long-lasting tolerance is acquired, therapy may be discontinued. Allergen extracts can be obtained from different sources, such as cat hair and pelt, mites, different types of pollen, venom protein, foods, etc. Allergy vaccines are currently the only effective therapy that can stop the progression of the illness because treatment with anti-inflammatory drugs, such as anti-histaminic drugs or corticoids, mitigates the symptoms of the allergic processes but does not modify the natural course of the disease 202,203 .

    AIT has been shown to induce the activation of antigen-specific Tregs and IL-10-producing Bregs (Br1) subtype cells, which is combined with anergy caused by Th2 cells 201 and the production of allergen-specific IgG antibodies that can compete with IgE for binding to allergens 204 .

    In the past, most vaccines were developed using natural allergen extracts. However, significant progress has been made in recent years to correctly characterize the allergen at the molecular level, and some of these allergens are now being produced by recombinant technologies, nucleic acid-based strategies, or synthetic peptide chemistry 205 .


    Another therapeutic approach for vaccines is in the field of cancer. Therapeutic cancer vaccines that contain self- or nonself-patient tumor lysates, viral vectors, mutated tumor proteins or peptides, among other types 206 administered in the presence of adjuvants can activate the immune system to induce antitumoral responses 207 . The goal is to activate the Th and Tc cell compartments to expand specific cytotoxic T and NK cells directed against tumor cells.

    Some vaccines are more immunogenic than others, and this effect can be related to several factors, such as the types/numbers of genetic mutations in the tumor, expression of neoantigens, production of viral proteins, an immunosuppressive environment, lack of expression of histocompatibility complex molecules, etc., which together may explain the large variability in tumor elimination 208 . Therapeutic cancer vaccines are generally very safe, and major secondary effects have not been observed, although large differences in patient responses are detected. Moreover, this strategy may be used in conjunction with other complementary therapies 209 , such as monoclonal antibodies, chemotherapy or cellular therapy 209,210 . Several patients are currently taking part in clinical trials and are receiving therapeutic cancer vaccines against different types of tumors, such as lung ( Identifier: NCT04397926), prostate ( Identifier: NCT03525652) or pancreas ( Identifier: NCT04161755), using individual or combined therapies.


    In the case of therapeutic vaccines for autoimmune diseases, such as multiple sclerosis, diabetes, Myasthenia gravis or Guillain Barré syndrome, the intention is to induce tolerance to self-antigens through the activation of regulatory cells (Tregs and Bregs) and tolerogenic dendritic cells, thus avoiding the immune response to self-components 211 . Due to the large variety of autoimmune diseases, the different etiologies and extensive variability, even in the same type of disease, designing a vaccine that can be useful for a wide range of patients is very difficult.

    However, several researchers are obtaining good results in animal models with nanostructures and peptides that induce specific tolerance, and it is predicted that, in the near future, these types of therapies will be applied to patients suffering from autoimmune diseases (reviewed by Serra and Santamaria 212 ).

    Polyclonal antibodies (pAbs)—serotherapy

    The discovery of antibodies by Dr. E. von Behring and Kitasato 213 at the end of the XIX century highlighted the potential of antibodies to neutralize tetanus and diphtheria toxins. This discovery opened the way to exploring the potential clinical applications of conventional antiserum-containing polyclonal antibodies from immunized animals/humans 214 . This “serotherapy” was initiated by Dr. Roux and Dr. Yersin, who used anti-diphtheria serum to treat several children 215 . After this initial success, the use of serotherapy was increased for use against diphtheria and other diseases but also led to the identification of problems, such as immunogenicity with the formation of immune complexes (Arthus reaction), the variability and limitation of the antibody batches, the content of a mixture of classes and subclasses of antibodies with different biological activities, and their temporal effects. For all of these reasons, therapy with polyclonal antibodies was very much restricted to special cases, such as the use of gamma-globulins for the prevention of Rhesus (RH) maternal-fetal incompatibility and tetanus or snake venom toxicity 216 .

    With the identification of gamma-globulin-deficient patients by Dr. Bruton in 1952 217 , the use of immunoglobulins as therapeutic molecules for the treatment of humoral immunodeficiencies was initiated. However, some problems were encountered in the initial phases, mostly related to the serum preparation and aggregation/fragmentation of antibodies. Since their initial use, several efforts have been made to avoid impurities and to improve the purification process, and several commercial products are now available (as intravenous or subcutaneous preparations). Currently, many patients with humoral immunodeficiencies are successfully being treated to prevent them from catching infectious diseases. More recently, the therapeutic applications of immunoglobulins have expanded to other diseases, such as against COVID-19 caused by SARS-Cov-2 infection (see below), autoimmune disorders and Kawasaki syndrome in children 218 . The beneficial effects seem to be mediated by several immunological mechanisms, including viral neutralization, inhibition of inflammatory cells and activation of immune regulators 214 .

    Monoclonal antibodies (mAbs)

    The development of monoclonal antibodies (mAbs) by C. Milstein and G. Köhler in 1975 219 (Nobel Prize winners for Physiology/Medicine in 1984) changed medicine and immunology completely, along with many other disciplines. Monoclonal antibodies are produced from the fusion of two cells to generate a hybrid cell or hybridoma with two characteristics, i.e., the production of one specific antibody and immortality. Dr. Milstein is considered to be the father of modern immunology for his crucial contribution 220 . The development of many different mAbs has enabled the identification of new molecules and the development of more accurate diagnostic approaches specific, fast and inexpensive technologies processes for the purification/concentration of compounds and better and more specific therapy. mAbs can now be used against specific targets according to the concept of the “magic bullet”, a term coined by Dr. Paul Ehrlich at the beginning of the XX century (reviewed in ref. 221 ).

    Numerous different mouse and rat mAbs were produced against several molecules, but due to their murine origin, patients treated with these mAbs suffered from hypersensitivity and immune responses 222,223 . Thus, most mAbs currently used in clinical applications are linked to radioactive elements and used for diagnostic purposes (Table 2).

    In an effort to avoid immunogenicity, mAbs were subsequently modified by genetic engineering approaches to carry mostly sequences of human origin. Several research groups and companies developed chimeric and humanized mAbs (Table 2), and these mAbs included additional modifications, such as changes in the carbohydrates (glycosylation) and/or antibody regions, with the aim of improving their therapeutic action 224,225,226,227,228 . Moreover, fragments of recombinant antibodies (Fabs, single-chain Fvs, different V regions, fusion proteins, smaller antibodies, etc.) increased the variability of these potential therapeutic agents.

    The generation of fully human mAbs took more time due to technical difficulties and ethical issues therefore, researchers sought alternative methods to conventional approaches, such as the development of transgenic animals carrying human immunoglobulin genes using minilocus vectors, artificial yeast/human chromosomes or P1 vectors. The generation of knockout mice (in which mice lack Ig genes) and further crosses with transgenic mice carrying human antibody sequences led to the generation of mouse strains that were able to produce fully human mAbs 229,230 . Other initiatives, such as the generation of immunodeficient mice in which human bone marrow or libraries of recombinant phages carrying human variable genes were reconstituted, allowed the development of more fully human antibodies (Table 2). Sir Greg Winter, Nobel Prize winner in Chemistry in 2018 231,232 , became the pioneer of mAb humanization through the genetic engineering of an antibody (Campath 1), later developing a fully human antibody (antitumor necrosis factor alfa, TNF-a) using recombinant phage technology 225,233,234 . Several companies are currently developing human antibodies using these and new technologies (reviewed in 225,227,233,234 ).

    Since 1975, the list of approved mAbs for human therapy has continued to increase (Table 2), and many more mAbs are in clinical trials 235,236,237 . The versatility of mAbs is based on a different mechanism of action 238 :

    Neutralization/blocking of soluble elements. For example, the neutralization of cytokines (TNF-α) and growth factors (vascular endothelium growth factor) prevents the exhibition of their effects, i.e., inflammatory and angiogenic effects, respectively 239,240 .

    Complement activation. IgG/IgM antibodies activate the complement cascade by the classical route, which leads to the death of the target cell 241,242 .

    Cytotoxicity mediated by NK cells. NK cells can facilitate mAb killing of target cells. The mAb, after binding to a target cell, can attach to Fc receptors on the surface of NK cells to trigger the release of granzymes and perforin, thus inducing cell target death 243,244 .

    Induction of cell death by apoptosis. Certain mAbs directed against some membrane molecules can directly activate apoptosis 243 .

    Blocking activation signals. Antibodies can block some membrane receptors and avoid cell activation/proliferation activation/proliferation 243,245 .

    Carriers of toxins, pro-drugs, enzymes, and radioactive elements. mAbs are able to concentrate select compounds around target cells, providing a much more selective therapy than conventional chemo- or radiotherapy 244 .

    Check point inhibitors. Leading to a recent revolution in cancer therapy, the identification of several inhibitory molecules can be blocked by mAbs, thus leading to the activation and proliferation of antitumoral T cells. Molecules such as CTLA-4 and PD1 and its ligand PDL-1, maintain immune cells under controlled conditions. However, it is possible to reactivate the antitumoral immune responses by blocking some of these molecules with mAbs, either directed to only one of them or by using various antibodies in combination (for example, against CTLA-4 and PD1) 246 .

    The results obtained with these therapeutic mAbs against checkpoint inhibitors in some types of cancer have been amazing. For their contribution to the understanding of the roles of CTLA-4 247 and PD-1 248 , the Swedish academy gave the Nobel Prize in 2018 to Dr. J.P. Allison and Dr. T. Honjo, respectively 249 . However, this therapy is not efficacious in all types of cancers for several reasons, such as the expression of these and other checkpoint inhibitors in immune cells, the number of antitumoral cells in each patient, an immunosuppressant microenvironment, the rate of cancer mutations, and the expression of histocompatibility molecules.

    Recombinant proteins

    There is a large list of recombinant proteins that are currently being used for human therapy, including interleukin 2 (IL-2), interferons (IFNs) and GM-CSF.

    IL-2 was identified in 1976 as a growth factor for T lymphocytes, and soon after Dr. Rosenberg started to use it in antitumoral therapy 250,251 . Years later, in 1991, IL-2 was approved by the FDA for patients with metastatic renal cancer and in 1998 for the treatment of metastatic melanoma 251 .

    Interferon (IFN) was described in 1957 by Isaacs and Lindenmann 252 . The interferon family is the largest family of cytokines and is classified into three different types (I, II, and III). Type I IFNs (including IFN-α and IFN-β) exhibit several molecular actions that may be very relevant for use in therapy for a range of pathologies (such as autoimmune diseases and cancers) 253 . In 1986, the FDA approved human IFN-α2a and IFN-α2b for patients with hairy cell leukemia and later on for patients with multiple sclerosis. Since their initial use, these interferon species have been approved for many other diseases, including chronic hepatitis B and C, lymphoma, advanced melanoma, and as adjuvants together with other therapies for several types of cancers 254,255 .

    Another cytokine is GM-CSF, which activates the production of granulocytes and monocytes from bone marrow myeloid progenitors and has shown adjuvant antitumoral effects 256,257 . Other cytokines, such as IL-5, IL-7, IL-12, IL-15, IL-18, and IL-21 258,259 , are being tested in several clinical trials, and it is expected that some of them, either alone or in combination, can be used in future antitumoral therapy.

    Other recombinant proteins are already on the market, some of which are derived from antibodies, with some advantages such as small size, low immunogenicity and general ease of production. Examples are etanercept and abatacept (CTLA-4 Ig), which were approved by the European Medicines Agency in 2000 and 2007, respectively. The former is a chimeric protein that carries the external portion of the tumor necrosis factor (TNF) receptor linked to the IgG Fc region, which captures soluble TNF to block its inflammatory effects 260 . The latter example is a fusion protein that combines the extracellular portion of human CTLA-4 and IgG1 Fc. Abatacept is a competitive inhibitor that blocks T-cell activation and can be used in the treatment of inflammatory illnesses such as rheumatoid arthritis 261 .

    Cellular immunotherapy

    Natural killer (NK) and lymphokine-activated killer (LAK) cells

    Natural killer (NK) cells were described in the 1970s based on their capacity to eliminate tumor cells without prior sensitization, with differences observed compared with specific cytotoxic T cells (which are activated based on the recognition of the target cells) 262,263 . In 1985, Piontek et al. reported that NK cells have the ability to preferentially kill cells that had lost the expression of the major histocompatibility complex class I molecules 264,265 .

    Lymphokine-activated killer (LAK) cells are a heterogeneous population that includes not only NK but also NKT and T cells, which can be generated in an in vitro culture of peripheral blood mononuclear cells (PBMCs) in the presence of IL-2 266 . Dr. Rosenberg and collaborators carried out studies using these cells in the presence of IL-2 (reviewed by Rosemberg 251 ). These LAK cells showed good antitumoral responses in 22% of the melanoma patients who received them as therapy 250 . However, secondary effects such as liver toxicity and the expansion of the Treg population limited their therapeutic effect. Researchers started to design new recombinant IL-2 with some mutations to avoid the activation of Tregs 267 , with linking it to polyethylene glycol (PEG) to increase its half-life and efficacy 268 .

    Another cytokine described later, IL-15, showed similarities to IL-2 in many respects 269 , and it had some unique advantages, such as the capacity to activate NK and cytotoxic T cells (Tc) but not Tregs. IL-15 is being used in different versions (alone, as a heterodimer with receptor IL-15/IL15Ra or IL15Rα IgFc, or in an agonist complex with ALT-803) 269 and in combination with other therapies in several clinical trials (examples: NCT01021059, NCT03905135, and NCT03759184).

    More recently, researchers have focused their attention on other cytokines and combinations (such as IL-15, IL-12, and IL-18) 270 , which are able to activate NK cells in vitro and induce a good responses in animal models. In some human clinical trials, remission has been observed for patients with acute myeloid leukemia 271,272 , which broadens the options for the use of NK cells in the treatment of this pathology.

    The properties of NK cells reveal their versatility as treatments against tumors. NK cells are able to kill tumors through several mechanisms, including receptor-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and death receptor-mediated apoptosis, but they also secrete cytokines such as interferon gamma that enhance the antitumoral adaptive immune response. NK cell adoptive transfer (either autologous or allogenic NKs) is currently being tested in clinical trials for hematological diseases and solid tumors, and numerous research groups have recognized their potential in other situations, such as transplant rejection and pregnancy. NK cell lines, memory-like NK cells and stem cell-derived NK cells are additional types of cells that can be used for tumor immunotherapy 273 .

    Regarding other cellular therapies, NK cells as substitutes for T cells for use upon transformation with an chimeric antibody receptor (CAR) are being explored (see below).

    Dendritic cells

    Paul Langerhans identified dendritic cells in human skin in 1868 274 , but these cells were not named until 1973 by Dr. Ralph M. Steinman (Nobel Prize in 2011) and Dr. Zanvil A. Cohn, who chose the term because the cell morphology, with long extensions, resembles that of neuronal dendrites 275 . In humans, dendritic cells are obtained from different sources that vary in origin, maturation state and tissue distribution (skin, lymphoid tissue, circulating cells). Among the main types of dendritic cells, plasmocytoids are conventional myeloid DC1 and DC2, pre-DC and monocyte-derived dendritic cells. In the epidermis, there are three types: Langerhans cells (LC), monocyte-derived LC-like cells and inflammatory dendritic epidermal cells (IDECS) 276 . As indicated above, DCs are antigen-presenting cells and are the only cells that are able to activate naïve T lymphocytes. A subpopulation of DCs also carries out a process known as cross-presentation. In this way, they facilitate the activation of both helper and cytotoxic T lymphocytes 277 . In addition to their participation in the immune response, they can be used in antitumoral therapeutic vaccines 277,278 .

    It is possible to generate a type of blood monocyte-derived dendritic cell in the presence of a mixture of cytokines in culture 279 —a process that induces their subsequent maturation and activation in the presence of tumor antigens (cell lysates, recombinant or purified antigens, peptides, RNA, DNA, and viral vectors 280 ). These cells can also be obtained from bone marrow hematopoietic CD34 + progenitor cells 281 . Other sources, such as circulating or skin dendritic cells, are relatively scarce and are therefore not usually used.

    After their differentiation and activation in vitro 278,282 , DCs are exposed to tumor antigens and infused back into the patient (either by blood infusion or injected into areas near the lymph nodes or even directly into them) to reach the secondary lymphoid organs as soon as possible, at which point they can present antigens to the T cells. This approach is a type of individualized therapy and is therefore expensive.

    The first approved vaccine in which autologous dendritic cells were used was Sipuleucel-T (Provenge) 283 , which was a treatment for prostate cancer refractory to hormonal treatment. Immunotherapy with dendritic cells is currently being tested in more than 200 clinical trials for various tumors: brain, pancreas, mesothelioma, melanoma and many others ( Identifiers: NCT01204684, NCT02548169, NCT02649829, and NCT03300843, respectively). The data indicate that the therapy is well tolerated and has led to increased patient survival in some trials. Furthermore, complete cure and partial remission outcomes have also been observed. The lack of efficacy on other tests was probably due to the presence of immunosuppressive factors in the tumor environment.

    Another therapeutic use of dendritic cells involves their induction of immunosuppression both in transplants and in autoimmune diseases 284 . In an autoimmune pathology such as multiple sclerosis, the intention is to achieve stable tolerogenic dendritic cells that can act against some autoantigens (such as myelin peptides) in the presence of vitamin D3, dexamethasone, or other agents 285 . Phase I clinical trials have generally shown good tolerance to this therapy without serious adverse effects 286 .

    However, greater control of this treatment is necessary in several respects to obtain the best therapeutic results 284 e.g., the type of dendritic cells and ex vivo differentiation, the antigens used, and the injection route are important considerations.

    Gamma/delta T cells (Tγ/δ)

    Human T cells expressing γ/δ TCR cells have interesting properties, including the capacity to kill a broad range of tumor cells. The advantages of these cells in cancer therapy are based on their independence from MHC expression on tumor cells and that their relative insensitivity to some inhibitor molecules (such as PD-1). The initial clinical application, with the adoptive transfer of autologous Vδ2+ cells after ex vivo expansion, showed only sporadic responses 287 , and different exploratory studies are currently being carried out to increase their clinical therapeutic use. Allogeneic Vδ2+ cells are also being explored in cancer therapy e.g., they are being used against refractory hematological malignancies 288 and advanced cholangiocarcinoma 289 .

    Regulatory T cells (Tregs)

    Although the basis of immune regulation was suggested centuries ago, regulatory T cells were described by Sakaguchi et al. as CD4+ CD25+ natural regulatory T cells 290 that expressed the forkhead box P3 transcription factor (foxp3) 291 . Later, induced or adaptive regulatory T cells were also identified, including different subsets that carry several phenotypic markers and express various cytokine secretion profiles 292 . All of these factors play crucial roles in the maintenance of immunological self-tolerance by suppressing autoreactive T cells.

    The manipulation of Tregs to achieve therapeutic outcomes is a field of great interest, because of both their expansion and activation in diseases, such as allergic and autoimmune diseases, and as a potential targets for cancer immunotherapy 293 .

    Tumor-infiltrating lymphocytes (TILs)

    Lymphocytes that infiltrate solid tumors are called tumor-infiltrating lymphocytes (TILs). In 1957, Thomas and Burnet proposed that the immune system performs tumor immune vigilance, with lymphocytes as sentinel cells leading to the elimination of somatic cells transformed by spontaneous mutations 294,295 .

    Since the end of the 1980s, Dr. Rosenberg has been trying to prove and improve the effective use of TILs. The process starts with surgery and the isolation of TILs from a tumor, followed by TIL activation in culture in the presence of cytokines, cellular expansion and, finally reinfusion into the patient. Since its inception, this therapy has been improved markedly, with an increase in optimal responses from less than 30% to the current 50–75%, in some cases. These higher success rates are due, in particular, to the prior preparation of the patient, including the depletion of lymphoid tissues, to avoid an expansion of regulatory cells 296 , myeloid suppressor cells and other cells that can compete with the transferred TILs.

    Currently, there are more than 200 trials in which TILs are being used alone or in combination with other immunotherapies on several tumors, such as melanoma, metastatic colorectal cancer, glioblastoma, pancreatic cancer, hepatobiliary cancer, ovarian cancer and breast cancer. This individualized therapy has limitations it can only be used on solid tumors, and the number and specificity of the TILs and the type of tumor and microenvironment make standardizing this therapy difficult.

    Chimeric antigen receptor (CAR)

    Since TILs include a variety of T lymphocytes with different specificities, the next step was to obtain T cells of a single type (monoclonal cells) carrying a clonal receptor capable of recognizing tumor antigens. This effort was carried out for the first time in mice and subsequently, in 2006, in humans with a transgenic TCR against the MART-1 melanoma antigen 297,298 . These types of receptors are known as tTCRs, but their ability to recognize antigens is restricted since they can only identify the peptides presented by antigen-presenting cells on self-histocompatibility molecules.

    This situation changed because of one of the latest revolutions in antitumor therapy, the development of T lymphocytes that carry a chimeric antigen receptor (CAR) based on a specific antibody directed to a target surface molecule 299,300 . These modified T cells can directly recognize tumor cells without required antigen processing or presentation by professional antigen-presenting cells. Moreover, the CAR includes all of the necessary elements for intracellular signaling and activation of helper and cytotoxic T lymphocytes.

    CAR therapy was developed by one of its pioneers, Dr. Carl June at the University of Pennsylvania in the United States 300 , who used modified T lymphocytes that carried a chimeric antigen receptor to target CD19+ leukemic B cells. After interacting with CD19+ cells, these modified CAR T cells were activated and able to proliferate and exert cytotoxic functions against target cells. In this case, both tumor and healthy B cells were affected. Although bone marrow continues to produce B lymphocytes, in cases of severe B lymphopenia, it is possible to provide exogenous immunoglobulins periodically.

    The whole process of the current CAR T-cell therapy begins with blood donation, from which lymphocytes are purified and genetically modified in vitro by a viral vector, which carries the genes coding for the chimeric antigen receptor. The cells are expanded in the presence of cytokines in culture and are subsequently reinfused into the patient. This type of cellular immunotherapy is individualized for each patient, with his/her CAR T cells ultimately destroying the tumor.

    Since the first generation of CARs appeared, namely, a chimeric receptor composed of an anti-CD19-specific single-chain variable fragment linked to a transmembrane domain and intracellular signaling domain of the T cell receptor (CD3 ζ chain), researchers started to modify the original design. New generations of CARs, including the CD3 ζ subunit together with other signaling domains, such as CD28, CD134, CD137 (4–1BB), CD27, and ICOS, or combinations (CD3 ζ, CD28, and CD134) 301 , have been developed in the second and third generations of CARs to improve several aspects, such as the activation, proliferation and survival of CAR T cells. The fourth generation of CARs show improved the antitumoral effects by carrying additional molecules (such as cytokines or drugs), improvements to the safety of CAR T-cell therapy through the use of suicide genes 301 and many new designs, such as dual CARs or the so-called split universal and programmable (SUPRA) CAR system 302 .

    In addition to T cells, other types of cells, such as NK cells, are now being explored for use in antitumoral responses 303 . In an effort to avoid using personalized treatment, researchers are now working on universal CARs that may be used on many different patients without inducing the problem of rejection 304,305,306,307 .

    The encouraging results obtained with this therapy have led to interest from companies, and some commercialized examples are available, although many more “in-house” or academia-produced CARs are in clinical trials. CAR T-cell therapy was initially designed for use against hematological cancers (leukemia and lymphomas), but many new opportunities have been opened for its use against solid tumors 308 , infectious diseases (such as HIV) 309 , allotransplantation, autoimmune diseases 310 and severe allergies 311 . China and the USA are the leading countries in producing CAR T-cell therapy, and numerous clinical trials are underway.

    Immunotherapy for COVID-19 patients

    Coronavirus disease 2019 (COVID-19), which is produced by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), affects millions of people in many countries. Most of the infected patients (80–85%) are asymptomatic or have mild symptoms, but the disease in some patients progresses to a moderate or severe illness that requires hospitalization in intensive care units because of respiratory distress, multiorgan failure, and/or other pathologies, and more than one-half million fatal cases have been reported worldwide. The most vulnerable population includes aging patients and those with comorbidities such as hypertension, diabetes and cardiovascular diseases.

    There are several aspects of the COVID-19 pathogeny that suggest an overreaction of the immune system in severely ill patients, with increased levels of inflammatory cytokines such as IL-6, IL-1 and others (creating the so-called “cytokine storm”), together with blood lymphopenia and CD8 T cell and NK cell exhaustion. Special therapies have not yet been identified to cure these patients, and preventive vaccines are not yet available, but some immunotherapies have been proposed as adjunct therapies, and some of these are currently in different phases of clinical trials 312 .

    The immunotherapeutic strategies include the following:

    Targeting inflammatory molecules. To attenuate the cytokine storm (IL-6 receptor, IL-6, IL-1, GM-CSF, VEGF, etc.), monoclonal antibodies against receptors and/or cytokines, receptor antagonists and/or inhibitors are proposed.

    Passive immunotherapy. Patients who were infected and recovered, but developed neutralizing antibodies against the SARS-Cov-2 virus, can donate plasma to treat severe/critical patients. Some reports have indicated promising results in a low number of patients who received convalescent plasma 313,314 , but conclusions cannot be drawn until several randomized studies and more patients are analyzed. In addition to the use of convalescence plasma, hyperimmune globulin therapy or monoclonal antibodies directed against the virus have also been proposed, and clinical assays are ongoing.

    Immunomodulation therapy. Intravenous immunoglobulins are aimed at blocking inflammation and preventing secondary infections 312 . This approach is being used with success in cases of Kawasaki syndrome in children.

    Cellular immunotherapy. To date, very little attention has been paid to the cellular immunotherapy approach in treatments of COVID-19, but several attempts may include the use of SARS-Cov-2-specific T and NK cells to trigger antiviral responses and autologous or allogenic Tregs to modulate inflammatory processes.

    Future challenges in immunotherapy

    Immunotherapy has been used for centuries, but only in recent years has this area expanded rapidly in several respects, mostly by the use of soluble elements (monoclonal antibodies and cytokines) and, more recently, with immune cells (cellular immunotherapy). There are many fields in which immunotherapy faces a range of challenges:


    1. Researchers are working on reducing the number of injections by employing a combination of vaccines. Several current vaccines contain components from 3–6 pathogens in a single injection, and these are able to provide adequate protection against all of these pathogens 315 .

    2. Researchers are developing more stable and durable vaccines. Improvements in the half-lives of vaccines, for example, by lyophilization, while maintaining immunogenicity is expected to reduce current problems, especially those involved in the transportation of vaccines to remote areas 316 . In this respect, nanotechnology can help in the design of more stable vaccines that lead to slow antigen release and improved immunogenicity 317 .

    3. Researchers are working on vaccines that confer protection against all serotypes of a specific pathogen (universal). This outcome is especially important for pathogens with high variability (such as the influenza virus). Researchers are designing vaccines that can protect against several variants by using common regions that can induce protective immune responses to all or most of the variants 318 .

    4. Researchers are developing alternative routes of administration (e.g., oral, inhaled, intranasal, skin, rectum, vagina) as substitutes for intramuscular or subcutaneous injections. One of the problems to be solved is the immune tolerance developed to elements delivered by the oral route, but some vaccines are already effectively administered by this route (such as the oral polio, cholera, typhoid fever and rotavirus vaccines). The intranasal route has also proven effective for some vaccines (nasal influenza vaccine), and vaccines administered through other routes are under investigation.

    5. Researchers are seeking the early protection of newborns 319 . Newborns are very susceptible to infections due to their immature immune system 320 . Moreover, the protection exerted by maternal antibodies transferred through the placenta during pregnancy against some pathogens interferes with the development of the newborn’s own immune response. Greater knowledge on ways to activate the immature immune system early will enable the development of vaccines for newborns. Moreover, immunization of pregnant women may help to enhance neonatal protection against several pathogens 321 .

    6. Researchers are developing new and more effective vaccines. This effort is crucial for very prevalent pathogens such as Mycobacteria tuberculosis, HIV virus or plasmodium falciparum. Although there are treatments against these pathogens, most are not curative—as in the case of HIV prevention is the best way to stop their spread.

    7. Researchers are working to address emerging pandemics. In the case of new pathogens, such as SARS-Cov-2, which has produced a recent global outbreak, effective vaccines are urgently required 322 . New technologies for vaccine formulations and routes of administration, the identification of immune-related factors of protection and modifications to the governmental regulatory and approval process for vaccines for emerging pathogens are challenges that must be faced to achieve a rapid vaccination procedure for outbreaks. Hundreds of vaccines against SARS-Cov-2 (using different strategies such as live attenuated or inactivated pathogens, viral vector-based, viral RNA, DNA, recombinant proteins, peptides, etc.) 323 are now under development, and some are in clinical trials. However, the need to develop a new vaccine in a short period of time should not negate the main principles of vaccination use: safety and immune protection.

    8. Researchers are working on genetic (RNA, DNA) vaccines because they have great advantages, including no requirement for growing a pathogen. Genetic vaccines can be obtained in a much shorter time, with much faster and safer production processes, and can be transported much more easily. However, the immunogenicity of these vaccines must be improved, and other problems need be avoided, such as the potential deleterious effects of integrating vaccine sequences into cells 324 .

    9. Researchers are developing safer and more powerful adjuvants. Many years ago, the only adjuvant authorized for vaccines was aluminum hydroxide (alum), but currently, several adjuvants are on the market 325 . The use of ligands that activate the innate immune response, such as those linked to TLRs or nanostructures with adjuvant effects, is currently under study.

    10. Researchers are boosting trained immunity, a new concept related to the innate immune memory-like described for NK cells (expansion) and macrophages (epigenetic modifications). Knowledge of how to handle trained immunity will enable better vaccine design and more effective secondary responses 326 .

    11. Researchers are seeking to eradicate diseases from the earth. The greatest challenge, eradicating disease is possible in the short term for some pathogens, such as poliovirus. Very few cases of polio have been recently reported, and these reports came from only three countries therefore, it is feasible that this disease can be eradicated in the near future.

    12. Advances are challenged by the anti-vaccine movement. Paradoxically, there are people who doubt the beneficial effects of vaccines, and they are putting the health of their own children and society in general at risk 327 . The effectiveness of community protection conferred through vaccinated people is disrupted by decreased numbers of immunized persons. This lesser coverage enables pathogens to infect the most susceptible people, such as small children, elderly patients and those who cannot be vaccinated due to certain pathologies or because they are undergoing immunosuppression treatment. Thus, news about the return of illnesses that were nearly forgotten, such as tetanus in Italy (the first case in 30 years), the death of a child in Catalonia from diphtheria, or the exponential increase of measles cases (already counted in the thousands) worldwide 328 , should make parents think carefully about the risks of not protecting children by vaccines. The World Health Organization ( argues that anti-vaccine movements can roll back all the achievements thus far in this field and have cited this issue as one of the main challenges to be resolved. Addressing the anti-vaccine movement requires a coordinated effort of professionals to inform parents adequately and perhaps other types of coercive measures that some countries are already applying (financial fines, denial of access to public assistance in childcare units, removal of authorization to travel/live in some countries, new laws, and so on).

    Antibodies and cytokines

    Immunotherapy with monoclonal antibodies has been a true revolution for many pathologies, as has the use of certain cytokines and recombinant fusion proteins. It is therefore predicted that these approaches may have a bright future, and regulatory agencies are expected to authorize many more mAb-based therapies in the coming years, especially given the good results obtained in clinical trials. Complete antibodies or those modified to increase their functionality or decrease their immunogenicity, combinations of antibodies and cytokines, antibody fragments, etc., are only some of the many possibilities for this type of product, which will expand the range of therapeutic options.

    One of the main problems regarding the use of antibodies in therapy, especially in cancer, is based on their often unpredictable efficacy. Large variability in terms of remission and durable clinical benefits between patients is observed (for example, in the antitumoral responses by antibodies directed to the checkpoint inhibitors). Thus, the main challenge is to understand the situations in which an antibody will have the desired effect. It is crucial to find validated biomarkers (with predictive and/or prognostic value) that can help to stratify or select patients for the best immunotherapy. A better understanding is also required for tumor heterogeneity, resistance to some drugs and immunosuppressive microenvironments 329 . An in-depth immunological study, together with a personalized approach, is certainly the way to improve the success of these types of therapies.

    In combination with conventional therapies (radiotherapy, chemotherapy, and surgery), other immunotherapeutic drugs or cellular immunotherapies can also help to maximize the efficacy of this immunotherapy, but increases in toxicity will be another challenge to face.


    The use of oncolytic viruses (OVs), bacteriophages that selectively infect bacteria, modified pathogens for vaccines or for antitumor immuno-activation, and the manipulation/ modification of the microbiota are some of the therapies that are being considered.

    OVs are designed to kill tumor cells and to activate the immune system against those cells. However, many of OVs have shown limited therapeutic effects when applied in monotherapy therefore, much more work is required to improve their systemic antitumor effects and avoid the attenuation of the virus, which limits the viral replication. Several obstacles, such as low viral delivery and spread, resistance to therapy and antiviral immunity, have been observed 330 . Thus, the main challenges with oncolytic viruses are addressed by improving their antitumoral efficacy, including the optimization of viral delivery, the development of OVs engineered to activate the immune system (e.g., by releasing cytokines), and their use as adjuvant therapies or in combination with other immunotherapeutic agents, such as immunomodulators 331 .

    Regarding gut microbiota manipulation as a therapeutic approach, fecal microbiota transplantation is an effective therapy for recurrent Clostridium difficile infection 332 and is now being investigated for other indications, such as inflammatory bowel disease and cancer. Some of the challenges facing microbiome transplantation are the lack of precise knowledge about the complete microbiome and the mechanisms of action involved in its therapeutic capacity, the large variability of its effectiveness and the external factors that affect it. More studies are centered on understanding how to manipulate bacterial colonies, the discovery of therapeutic molecules, nutrient competitions, etc., that are required for successful application. The best type of therapy (either individual or the combination of bacteria) is also under debate, along with how to reach the market by translating this individualized therapy into commercial scale products. The safety and potential adverse long-term effects are also being assessed.

    Other components (nanomaterials and small molecules)

    Nanomaterials. To obtain approval for the use of other elements from incipient fields, such as the use of different types of nanostructures, either alone or in combination with other immunotherapies, it is important to resolve certain issues. In the case of nanoparticle use, a better understanding of the interaction between nanomaterials and biological media nanoparticle biodistribution, metabolism and biocompatibility and the reproducibility of the synthesis and scaled up production of nanomaterials are among the issues to address.

    Small molecules. A greater knowledge of several molecules involved in the immune system has led to the development of new therapeutic agents, which have been synthesized by traditional chemistry and block or activate intracellular signaling. The low cost of production of these molecules, along with the scaling and reproducibility of small-molecule batches, has attracted the attention of pharmaceutical companies interested in a whole set of new immunomodulatory drugs. A better understanding of the mechanism of action of small-molecule-based drugs and proof that they offer higher efficacy than existing therapies, either in monotherapy or in combination therapy, are challenges that face those seeking to engineer new types of targeting molecules.

    Cellular immunotherapy

    To date, cellular immunotherapy has been an individualized therapy with high production costs, and it requires the involvement of multidisciplinary groups in hospitals. A real challenge in the field of cellular immunotherapy is the acquisition of universal off-the-shelf cell therapies to replace those currently made to order in a very personalized manner. The development of universal cells, for example, in the case of CAR T-cell therapy, would increase the number of patients who could benefit from this treatment at thus reduce the costs.

    Other challenging aspects of cellular immunotherapy are the life-threatening toxicity of induced and their lack of effect on solid tumors, which is mostly due to the immunosuppressive tumor microenvironment. This approach requires new strategies to overcome these difficulties. In addition to cancer, cellular immunotherapy has a long history of use against autoimmunity, infectious diseases, allergies and transplantation rejection. It is also important to find biomarkers for prognosis/prediction that can help to optimize this method. Other therapies that involve the use of activated NK cells, tumor-infiltrating lymphocytes, vaccination with dendritic cells, etc., are having partial clinical success. Similar to other treatments, these approaches require further study, but it is feasible that they may become reality in the near future.

    All the differences between COVID-19 vaccines, summarized in a simple table that you can take to your vaccination appointment

    Coronavirus vaccines are the world's escape route out of a pandemic that has shut down schools, grounded flights, and left millions dead.

    Vaccines from Moderna, Pfizer-BioNTech, AstraZeneca-Oxford University, and Johnson & Johnson have been approved in the West. In the US, all of them have been authorized except AstraZeneca's. In the UK, all of them have been authorized.

    Each is given as a shot in the muscle of the upper arm.

    You might not get a choice about which COVID-19 vaccine you get, but all four offer some protection against severe illness, so the advice is to take one if you are offered it.

    For the two-dose vaccines, you should have two shots of the same one, where possible.

    Speak with your doctor if you are pregnant, breastfeeding, have a specific medical condition, or take medicines —especially if they thin your blood or affect your immune system. Experts have said the COVID-19 vaccines won't make you infertile. Side effects may start within a day or two and should go away within a few days.

    A rare adverse-event associated with AstraZeneca and Johnson&Johnson's COVID-19 shots include unusual blood clots. You should seek urgent medical attention if you have a persistent or severe headache lasting more than three days. Other symptoms to watch out for include: shortness of breath, chest pain, painful limbs and tummy pain.

    We've made a table that gives you the key information for each shot, whether you've booked an appointment or not. Scroll down to view it.

    Vaccine Insights

    Developing vaccines quickly and safely

    An interactive tool from our vaccine experts that explores how a vaccine is developed and the differences between a typical timeline and an accelerated timeline.

    Johns Hopkins International Vaccine Access Center

    VIEW-hub is a publicly available interactive tool that displays up-to-date information on vaccine characteristics, and vaccine introduction and use globally. Vaccines include COVID-19 as well as many childhood vaccines in routine immunization programs.

    Graham Hatfull

    Mycobacterium tuberculosis kills more people than any other single infectious agent. Since antibiotics are available and the BCG vaccine is in widespread use, why do two million people die each year from TB? The answer, in part, is that we really don't understand this curious bacterium or what parts of its genetic instructions make this such a deadly pathogen. At the heart of our strategies to understand mycobacterial genetics is the mycobacteriophages - viruses that infect the mycobacteria. These are easy to grow and manipulate and offer advantages over working with the slow-growing mycobacteria (such as M. tuberculosis) that can take up to a month to produce a colony on an agar plate. Phages are also rich sources of potential genetic and molecular tools that can be used to study - and to modify - their bacterial hosts.

    Here's just a flavor of some of the current studies going on in the lab:

    Exploring bacteriophage genomics. In collaboration with Dr. Hendrix we have spearheaded an initiative to understand viral diversity and evolution. Our specific focus is on the genomic characterization of mycobactriophages, and a collection of about 250 complete genome sequences have been determined. Many of these phages were isolated and sequenced through three programs in which phage discovery and genomics is a platform for integrating our science and educational missions. These are the Pittsburgh Phage Hunters Integrating Research and Education (PHIRE) program, the Howard Hughes Medical Institute Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (HHMI SEA-PHAGES) program, and a Univiersity of KwaZulu-Natal and KwaZulu-Nalat Research in TB and HIV (UKZN/K-RITH) workshop. These studies have not only provided valuable insights into phage diveristy and evolution, but present a rich and easily-accessible reservoir of genetic and mechanistic novelty for further study. A database of mycobaectriophage genomic infomration is available at

    Exploiting mycobacteriophages. We are dissecting the mycobacteriophages to understand the functional roles of the thousands of genes we have identified, and to deternine if and when they are expressed, and how this expression is regulated. We are exploiting this information to develop tools and approaches that not only generate new tools for genetic manipulation for tuberculosis, but also to gain advances in diagnosis, prevention and treatment of the disease.

    Site-specific recombination. Many if not most of the mycobacteriophages we have sequenced integrate their DNA into the host chromosome (and can excise them too). We are studying the mechanism of integrase-mediated site-specific recombination with a primary current focus on the serine-integrases. We are partiualrly interested in understanding how recomibnational directionality is determine in phage integration systems.

    Tools - Genetic and Clinical. Studying the mycobacteria and their phages has great potential for the development of novel tools for their genetics but also for a more direct clinical involvement. Two systems we have been involved in developing are multivalent recombinant BCG vaccines and Luciferase Reporter Phages, but there are numerous additional strategies awaiting further development!

    Total doses per 100 people

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    This information is regularly updated but may not reflect the latest totals for each country. Total vaccinations refers to the number of doses given, not the number of people vaccinated. It is possible to have more than 100 doses per 100 population as some vaccines require two doses per person.

    Source: Our World in Data, ONS, dashboard

    Last updated: 2 July 2021, 12:50 BST

    Watch the video: Ένζυμα - βιολογικοί καταλύτες (January 2023).