Definition and History of Vaccines
- A vaccine is an agent that is prepared from an antigen or pathogen by either deactivating its mechanisms of protein synthesis or denaturing or killing them. This allows the preparation of an agent that can be introduced into the host in order to induce an immune reaction with an ultimate protection end-game.
- The history of vaccines trails down to 1877 when Loise Pasteur developed a vaccine using a weakened strain of the anthrax bacillus, Bacillus anthracis. He adapted a methodology of attenuating the culture of anthrax bacillus by incubation at a high temperature of 42–43°C and inoculated the attenuated bacilli in the animals, demonstrating that animals receiving inoculation of such attenuated strains developed specific protection against anthrax.
- This concept was successfully demonstrated on a farm at Pouilly-le-Fort in 1881 by vaccinating sheep, goats, and cows with the attenuated anthrax bacillus strain. The result indicated that all the vaccinated animals survived an anthrax attack which the non-vaccinated could not, hence they died of anthrax.
- Louis Pasteur also developed the first vaccine against rabies in humans in 1885, and it saved millions around the globe.
- Pasteur coined the term vaccine in commemoration of Edward Jenner who used such preparations for protection against smallpox. This led to the establishment of various institutions in several countries in the world that prepared vaccines and studied infectious diseases such as the Pasteur Institute in Paris.
What are Vaccines? How do they work in the Immune System?
- Vaccines are biological preparations that are made up of killed or attenuated pathogens (virus or bacteria) or part of the surface of the antigen.
- The preparation is made in such a way that it can not cause disease on its own, but it helps the body to develop a memory type of immunity. This means that if an individual encounters or is infected by the same pathogen (whose part has been used to prepare the vaccine), the immunity will ‘remember’ and induce a more vigorous immune response against the pathogen.
- Initially, the innate immune response (primary response) elicited on the first encounter with a pathogen, is normally slow and that is why one will display symptoms of the disease before the immune system can elicit a reaction to kill the pathogen, and therefore the body develops an adaptive immune response (secondary response) through specialized immune cells which counter the pathogen and create a long-lasting memory.
- Therefore, vaccination or the introduction of a vaccine into the body will have a similar kind of immune reaction (secondary response) only that it will by-pass the slow initial response but enables the body to acquire immunity (from the vaccine). In other words, the vaccine tricks the body to believe that it has the disease, and therefore, able to fight the disease. This makes the body be able to kill the pathogen before it can have the chance to cause disease due to memory that is created from vaccination.
- Vaccination is the safest and most common way to gain immunity against bacteria or viruses that your body has yet to encounter.
- Generally, a vaccine works as follows:
- Administration of vaccine which contains antigens for a specific disease or pathogen
- Identification and recognition of the antigen in the vaccine as foreign, by the immune system
- Development of antibodies by the immune system to neutralize the antigens.
- Storage of these immune effector antibodies as memory antibodies for future response in case an individual is exposed to the live pathogen or disease.
- Significantly, vaccination is done to prevent diseases and wipe them out in eventuality. Administration of a vaccine to a significant proportion of a population.
- Vaccines are given to prevent and eventually wipe out diseases. When a vaccine is given to a significant portion of the population, it protects those who receive the vaccine as well as those who cannot receive the vaccine. This concept is called “herd immunity.” When a high percentage of the population is vaccinated and immune to a disease, they do not get sick — so there is no one to spread the disease to others. This herd immunity protects the unvaccinated population from contagious (spread from person to person) diseases for which there is a vaccine.
Types of Vaccines and Their Characteristics
- Vaccines have proved to have a strong defense against some of the most fatal diseases and if they were still unavailable, the survival of individuals would be based on their immune defenses which could either resolve the infection or lead to death from the infection.
- Therefore, the use of vaccines means, the vaccine will mimic the pathogen and cause an immune response that is similar to that that can be activated by the pathogen.
- Historically, these vaccines have eliminated fatal infections such as smallpox, and almost eliminated polio, and saved many individuals from typhus, tetanus, hepatitis A and B, measles, and rotavirus diseases, etc.
- However, still successful vaccines are yet to be developed for many deadly diseases that cause chronic infections such as AIDS, hepatitis C, tuberculosis, malaria, and herpes
- Successful vaccines against these chronic diseases must be able to stimulate immune responses that are similar to those resulting from most natural exposures to the pathogen but still remains a challenge.
- Various vaccines have been designed and here is a detailed approach to how these vaccines have been developed, those in use, and those still under experimentation.
- Major advances in understanding the complexities of the interaction of pathogens or microbes with the human host have revolutionized vaccine developments and advances in recent times. Coupled with advances in laboratory techniques and technologies, have aided the development of new vaccine types.
- Some more developed approaches such as vaccinomics, which is the application of genomics and bioinformatics to vaccine development, is a new approach that may solve the problem of developing vaccines against microbes and parasites.
- Vaccine types can broadly be classified into three groups:
- Whole-organism Vaccines
- Subunit Vaccines
- Nucleic Acid Vaccines
Many vaccines that were developed early consist of an entire pathogen that is either killed (inactivated) or weakened (attenuated) so that they cannot cause disease. They are known as the whole-organism vaccines. These vaccines elicit strong protective immune responses and many vaccines used today are prepared in this manner, but not all disease-causing microbes can be effectively targeted with a whole-organism vaccine.
1. Inactivated (Killed) Vaccine
- These were produced by killing the pathogen (bacteria, virus, or other pathogens) with chemicals or heat, or radiation.
- The killed pathogen can not cause disease, and this means that they do not replicate in the host’s body.
- Advantage: These vaccines are stable and safer than the live attenuated vaccines
- Disadvantage: The major disadvantage of this type of vaccine is that it elicits a weaker immune response and therefore, it requires more vaccine dosages and a booster dose as well, so as to confer protective immunity.
- Examples of Inactivated Vaccines include poliomyelitis (sulk vaccine), rabies, typhoid, cholera, pertussis, pneumococcal, rabies, hepatitis B, and influenza vaccines.
2. Live-attenuated vaccines
- These vaccines were developed in the 1950s where advances in tissue culture techniques were developed.
- These vaccines are prepared from a whole-organism, by weakening their pathogenicity so that they can not cause disease but can induce an immune response, hence the term attenuation.
- These vaccines elicit strong immune responses because they are similar to the actual disease pathogen and hence they confer a life-long immunity after only one or two doses, therefore they are very effective.
- They are also relatively easy to create for certain viruses, but difficult to produce for more complex pathogens like bacteria and parasites.
- Disadvantages: There is a remote chance that the weakened germ can mutate or revert back to its full strength and cause disease.
- Live attenuated vaccines should not be given to individuals with weakened or damaged immune systems.
- To maintain potency, live attenuated vaccines require refrigeration and protection from light.
- Examples include Measles/Mumps/Rubella (MMR) and Influenza Vaccine Live, Intranasal (FluMist®), Polio (Sabin vaccine), Rotavirus, Tuberculosis, Varicella, Yellow fever.
- The attenuated strain of Mycobacterium bovis called Bacillus Calmette- Guérin (BCG) was developed by growing M. bovis
on a medium containing increasing concentrations of bile. After 13 years, this strain had adapted to growth in strong bile
and had become sufficiently attenuated that it was suitable as a vaccine for tuberculosis.
3. Chimeric vaccine
- The evolution of modern genetic engineering techniques has enabled the creation of chimeric viruses, which contain genetic information from one viral particle and display biological properties of different parent viruses.
- An NIAID-developed live-attenuated chimeric vaccine consisting of a dengue virus backbone with Zika virus surface proteins is undergoing early-stage testing in humans.
Whole-organism vaccines, whether alive or dead, have another big drawback. Considering that they are composed of complete pathogens, they retain molecules that are not involved in evoking immunity, including unavoidable byproducts of the manufacturing process such as contaminants which can trigger allergic or immune disruptive reactions.
- These are vaccines that are prepared by using components or antigens of the pathogen. These components can stimulate the immune system to elicit appropriate immune responses.
- They are also known as acellular vaccines because they do not contain a whole cell, but just part of a cell of the bacteria or virus.
- These vaccines were produced to cub the inefficiencies of the live attenuated and killed vaccines prepared from whole-organisms such as adverse reactions associated with the vaccines and the mutations that may lead to the virulent strains of the pathogens.
- The subunit vaccines are safe and easier to produce, however, they require the use of an adjuvant in order to produce a stronger protective immune response. This is because an antigen alone can not be able to produce sufficiently enough long-term immunity.
- One of the earliest vaccine produced against pertussis was an inactivated Bordetella pertussis bacteria preparation in the 1940s, but this vaccine caused minor adverse reactions such as fever and swelling at the injection site, hence the vaccine was avoided leading to a decrease in its vaccination and therefore an increase in cases of pertussis infections. This led to the development of acellular pertussis vaccines that were based on purified B.pertussis components. These newly prepared vaccines had no adverse reactions associated with their administration.
Some of the subunit vaccines produced to prevent bacterial infections are based on the polysaccharides or sugars that form the outer coating of many bacteria. Therefore, there are subtypes of subunit vaccines as follows:
1. Polysaccharide Vaccine
- Some microbes contain a polysaccharide (sugar) capsule which they use for protection and evading the human immune defenses, especially in infants and young children.
- Therefore, these are vaccines that are prepared using the sugar molecules, polysaccharides from the outer layer of a bacteria or virus.
- They create a response against the molecules in the pathogen’s capsule. Normally these molecules are small hence they are not immunogenic (can not induce an immune response on their own). Hence, they tend to be ineffective in infants and young children between 18-24 months, and they induce a short-term immunity associated with slow immune responses, slow activation, and it does not increase of antibody levels and it does not create an immune memory.
- Therefore, these sugar molecules are chemically linked to carrier proteins and work similarly to conjugate vaccines.
- Examples of polysaccharide vaccines include Meningococcal disease caused by Neisseria meningitidis groups A, C, W135, and Y, as well as Pneumococcal disease.
2. Conjugated Vaccines
- These vaccines are prepared by linking the polysaccharides or sugar molecules on the outer layer of the bacteria to a carrier protein antigen or toxoid from the same microbe.
- The polysaccharide coating disguises a bacterium’s antigens so that the immature immune systems of infants and younger children cannot recognize or respond to them.
- Conjugate vaccines get around this problem through the linkage of polysaccharides with a protein.
- This formulation greatly increased the ability of the immune systems of young children to recognize the polysaccharide and develop immunity.
- The vaccine that protects against Haemophilus influenzae type B (Hib) is a conjugate vaccine.
- Today, conjugate vaccines are also available to protect against pneumococcal and meningococcal infections.
3. Toxoid Vaccines
- These vaccines are prepared from inactivated toxins, by treating the toxins with formalin, a solution of formaldehyde, and sterilized water.
- This process of inactivation of toxins is known as detoxification and the resultant inactive toxin is known as a toxoid.
- Detoxification makes the toxins safe to use.
- The toxins used for the preparation of toxoids are obtained from the bacteria that secrete the illness-causing toxins.
- This means that when the host body receives the harmless toxoid. the immune system adapts by learning how to fight off the natural bacterial toxin responsible for causing illness, by producing antibodies that lock onto and block the toxin.
- Examples of toxoid vaccines include diphtheria and tetanus toxoid vaccines.
4. Recombinant Protein Vaccines
- After the start of the generic engineering era, recombinant DNA technology also evolved. This is where DNA from two or more sources are combined. This technology harnessed the development of recombinant protein vaccines.
- For recombinant vaccines to induce immunity against a pathogen, they have to be administered along with an adjuvant or expresses by a plasmid or a harmless bacterial or viral vectors.
- Production of these recombinant protein vaccines involves the insertion of DNA encoding an antigen such as a bacterial surface protein, which stimulates an immune response into bacterial or mammalian cells, expressing the antigen in these cells, and then the antigen is purified from them.
- Recombinant protein vaccines allow the avoidance of several potential concerns raised by vaccines based on purified macromolecules. For example, the presence of contaminants in vaccines after purification may cause potential harm to the host.
- The production of recombinant vaccines also allows the production of sufficient quantities of purified antigenic components.
- The classical example of recombinant protein vaccines currently in use in humans is the vaccine against hepatitis B. The vaccine antigen is a hepatitis B virus protein produced by yeast cells into which the genetic code for the viral protein has been inserted.
- Vaccines that are also used to prevent human papillomavirus (HPV) infections are also based on the recombinant protein antigens, by preparing from the proteins of the outer shell of HPV, which forms particles that almost resemble the virus.
- The virus-like particles (VLPs) prompt an immune response that is similar to that elicited by the natural virus, and they are non-infectious since they do not contain the genetic materials that the virus needs to replicate inside the cells.
- An experimental recombinant protein vaccine for chikungunya fever has also been designed by the National Institute of Allergy and Infectious Disease (NIAID).
5. Nanoparticle vaccines
- This vaccine development was based on a strategy to present protein subunit antigens into the immune system.
- The NIAID has also designed a universal flu vaccine, an experimental vaccine with protein ferritin which can self-assemble into microscopic pieces known as nanoparticles that display a protein antigen.
- A nanoparticle-based influenza experimental vaccine is also being evaluated in human trials (early-stages).
- This new technology of vaccine delivery is also being evaluated and assessed for the development of vaccines against MERS coronavirus, respiratory syncytial virus (RSV), and Epstein-Barr virus.
Recent advances in the subunit vaccine development and delivery systems include solving the atomic structures of proteins. For example, NIAID has been able to solve the 3-D structure of a Respiratory Syncytial Virus (RSV) surface-bound to an antibody, identifying a key part of the protein that is highly sensitive to neutralizing antibodies. They were then able to modify the RSV protein to stabilize the structural form in which it displays the neutralization-sensitive site.
- Subunit vaccines are also being developed to offer broad protection against various infections such as malaria, Zika, chikungunya, and dengue fever.
- The experimental vaccine, designed to trigger an immune response to mosquito saliva rather than a specific virus or parasite, contains four recombinant proteins from mosquito salivary glands.
Nucleic Acid Vaccines
- These are vaccines designed to aim at introducing the genetic materials that code the antigen or the antigen that is aimed at inducing an immune response, enabling the host cells to use the genetic materials to produce the antigens.
- The advantages of the nucleic acid vaccine approach include:
- stimulating a broad long-term immune response
- excellent vaccine stability
- ease of large-scale vaccine manufacture
- rapid production
- reduces potential risks of working with the live pathogen
- encoding only the key antigen without including other proteins
- The advantage of the ease of production is a potential game-changer for targeting epidemic or emerging diseases where rapidly designing, constructing, and manufacturing the vaccine are crucial
Some of the know nucleic acid vaccines models include:
1. DNA plasmid vaccines
- These are vaccines that are composed of a small circular piece of DNA known as a plasmid. The plasmid carries genes that encode proteins from the pathogen of interest.
- Experimental DNA plasmid vaccines that have been designed by the National Institute of Allergy and Infection Disease (NIAID) to address some viral disease threats including SARS coronavirus (SARS-CoV) in 2003, H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and Zika virus in 2016.
2. mRNA vaccines
- mRNA is an intermediary between DNA and protein. Recent technological advances have developed mRNA vaccines overcoming the instability issues of mRNA and its delivery into the cells, with encouraging results.
- Some experimental mRNA vaccines have been designed to protect mice and monkeys against Zika virus infection, administer in a single dose.
3. Recombinant vector vaccine
- These are vaccines designed as vectors or carriers using harmless viruses or bacterium and they introduce the genetic material into cells.
- Majorly these vaccines are designed and approved for use to protect animals from infectious diseases, including rabies and distemper, but some have been developed to protect humans from viruses such as HIV, Zika virus, and Ebola virus.
Immunization Schedules for Children and Teenagers according to the National Academy of Pediatric
|1.||Bacille Calmette–Guérin- BCG||At birth||Administered intradermally; No booster|
|2.||Oral Polio vaccine- OPV||At birth (zero doses)
6 weeks (1st dose)
10 weeks (2nd dose)
14 weeks (3rd dose)
|Administered orally; boosters between 16-24 months|
|3.||Diphtheria, pertussis, tetanus- DPT||6 weeks (1st dose)
10 weeks (2nd dose)
14 weeks (3rd dose)
|Administered intramuscularly; booster dose at 16-24 months|
|4.||Diphtheria and tetanus toxoids DT||5 years||Administered intramuscularly, they are booster doses|
|5.||Tetanus toxoid – TT||10 years
|6.||Rotavirus vaccine (Rotarix and RotaTeq)||6 weeks
|7.||Haemophilus influenzae type B vaccine (Hib)||6 weeks
|8.||Measles Vaccine||9 – 12 months||Administered Intramuscularly|
|9.||Human Papillomavirus||11-12 years||Administered intramuscularly in the deltoid region of the upper arm or the higher anterolateral area of the thigh.|
Update: COVID-19 Vaccine Progress with examples of Candidate Vaccines
- The occurrence of the SARS-CoV-2 viral infection pandemic known as COVID-19 has had scientists racing to produce a vaccine that will help protect the globe from future infections of the virus and also protect those who have not been infected as well.
- However the long process of vaccine production, COVID-19 pandemic has brought about the urgency to produce a reliable, effective vaccine to safeguard the lives of many in the future upon the rise of infections over the past couple of months globally.
- The aim of vaccine production for protection against COVID-19 causative agent, SARS-CoV-2 is to induce a strong immune response against the virus, and it’s not to treat the infection. Therefore, the discovery of a COVID-19 vaccine will mean protection against future infections.
- Currently, there are over 100 vaccine candidates, with 55 vaccines that are being tested, all prepared using different methods and technologies and at least 87 preclinical vaccines are actively being investigated in animals.
- Many of the COVID-19 vaccines are on trial and presently, there is no vaccine that has been authorized for emergency use by the Food and Drug Agency (FDA). However several of these vaccines are through to the third phase of the trial
Examples of vaccines that are on trial include:
mRNA-1273 produced by Moderna
- Moderna is an American company that produces vaccines based on mRNA vaccine technology to produce viral proteins in the body.
- The new COVID-19 vaccine, mRNA-1273 contains genetic instructions for building a coronavirus protein, known as a spike. When the vaccine is introduced into cells, it causes the cells to make spike proteins, which are then get released into the body provoking an immune response.
- They started producing the vaccine in January, and by March the vaccine had shown promise for protection of monkeys against the novel coronavirus and they put the vaccine for a human trial. By July, they were on the third phase of the clinical trial with 30,000 volunteers.
- Early Nov, the preliminary results of the trial had shown 94.5% efficacy.
- Nonetheless, they have had a few hiccups on questions of the patent for vaccine development technology including that of the novel coronavirus, of which they claimed they can not actualize that their patent innovation is the first to be produced however, they have made deals with several countries including USA, Canada, Qatar, and Japan to supply their vaccine if approved.
BNT162b2 vaccine by Pfizer and BioNTech
- Pfizer a US-based company in collaboration with BioNTech, a German company are so far the most ahead companies to have coined a COVID-19 vaccine with preliminary data of over 90% effectiveness and being the first companies with such outstanding results, this far.
- These companies are also using mRNA technology and have developed the BNT162b2 vaccine.
- The vaccine candidate is administered intramuscularly by injecting snippets of the virus genetic material (mRNA) into the human cells.
- This activates the host cells to produce viral proteins mimicking the coronavirus, hence trains the immune system to recognize its presence.
- The vaccine requires two doses that are taken 21 days apart and its mechanism involves the production of antibodies and T-cell responses specific to SARS-CoV-2 proteins as per the preliminary results.
- On 20th Nov, the announced that they have filed for Emergency Authorization Use submission to the FDA based on the vaccine efficacy rate of 9% demonstrated by the companies on their phase 3 clinical study using a group of participants (without prior infection to the virus as the first primary objective and participants with and without prior infection to the virus as the second primary objective).
- The participants were checks and immune responses measured 7 days after the second dose of the vaccine.
- The participant population of 44,000 people globally with diverse racial and ethnic backgrounds, has indicated no serious safety concerns to the vaccine according to the Data Monitoring Committee (DMC)
- Pfitzer has launched a delivery pilot program to deploy the vaccines to four US states including Rhode Island, Texas, New Mexico, and Tennessee.
- Produced by a Russian based institution called Gamaleya National Center of Epidemiology and Microbiology, it is a viral vector vaccine that uses a weakened version of the common cold-causing adenovirus to introduce SARS-CoV-2 spike proteins into the body.
- The vaccine uses two strains of adenovirus, and it requires a booster injection after 21 days of the initial injection. From recent publications the Lancet, the vaccine has shown to produce antibodies and T-cell immune responses
- The institutions announced its interim analysis of its phase three trial to be 92% efficacy but the participant numbers were too few (29) to be convincing.
- This another candidate vaccine that has been developed by Bharat Biotech, an Indian biotechnology company, in collaboration with the Indian Council of Medical Research and the National Institute of Virology.
- The COVAXIN vaccine is prepared using an inactivated or non-infectious form of the coronavirus, to mean that it can no longer cause disease but it has the ability to provoke an immune response.
- The vaccine requires a booster dose administered 14 days after the first dose. The vaccine has shown to produce antibodies in monkeys and in October, preliminary results seemed to indicate that 90% of human participants developed antibodies.
Other candidate vaccines include:
- NVX-CoV2373 a recombinant protein vaccine by Novavax, a biotechnology company based in Gaithersburg, Maryland.
- JNJ-78436735 an adenovector vaccine by Johnson and Johnsons based in New Jersey
- CoronaVac an inactivated vaccine by Sinovac a Chinese pharmaceutical company in collaboration with a Brazillian research center Butantan
Side Effects of Vaccines
- The effects of vaccines are normally mild and go away within hours to days of administration. Intravenously administered vaccines can leave a sore pain on the site of administration but it goes away after a few hours or days, on their own.
- However, the effects may vary from individuals most side effects of vaccination can be mild including soreness, swelling, or redness at the injection site, fever, rashes, and achiness to serious effects including seizure or life-threatening allergic reaction, but they are rare.
- Many infants and children will experience a medical event of close proximity to vaccination, which may or may not be related to vaccination. According to the Food and Drug Administration (FDA) and the Center for Disease Control (CDC), monitoring and analyzing the adverse effects of vaccination in children.
- Some of the mild effects include:
- Pain, swelling, or redness where the shot was given which may last 2-4days
- Mild fever and chills that lasts for a few hours and it occurs in 70% of all the vaccinated children
- Muscle and joint aches
- Note that, some of these effects arise as a sign of the bodybuilding up immunity against a disease.
- Serious or adverse side effects are rare but may occur in 1 to 1million people, and they may include:
- Serious eye infection, or loss of vision, if the vaccine spreads to the eye eg smallpox vaccine.
- Rashes may occur on the entire body in 1 per 4,000 people.
- Severe rash on people with eczema in 1 per 26,000.
- Severe brain reaction or Encephalitis, which can lead to permanent brain damage occurring in 1 per 83,000.
- Severe infection beginning at the site of vaccination occurring in 1 per 667,000, mostly in people with weakened immune systems.
- Death occurring in 1-2 per million, mostly in people with weakened immune systems.
- For every million people vaccinated for smallpox, between 14 and 52 could have a life-threatening reaction to the smallpox vaccine.
- Examples of vaccines and their effects
- Haemophilus influenza type B vaccine is well known for its potential side effects. Haemophilus influenza type B is a bacterium that can cause serious infections, including meningitis, pneumonia, epiglottitis, and sepsis, and it is recommended that children receive the Hib vaccination as early as 2 months old. Some of the known side effects include:
- Redness, warmth, or swelling where the shot was given (up to 1 out of 4 children)
- Fever over 101°F (up to 1 out of 20 children)
- Smallpox is a fatal infection that has a 30-40% fatality rate and it is caused by Variola major or Variola minor virus and its vaccination is done mainly to military personnel and people who are first responders in the event of a bioterror attack. Some of the side effects of the smallpox vaccine include rashes, redness, and tenderness on the site of administration, fever, headaches, loss of vision, brain damage (encephalitis), and even death.
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