OVERVIEW OF VACCINES

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Vaccines are biological substances that contain attenuated microorganisms or microbial preparations and/or antigens to a particular infectious disease agent, and which are used to protect an individual against the disease or infection in future. They are usually suspensions of weakened, killed or fragmented microorganisms or toxins (usually derived from microbes) administered primarily to prevent diseases or infection in living systems including man and animals. The medical procedure of administering these vaccines to humans or animals is generally known as vaccination. Vaccination is simply defined as the administration of vaccines to a living host, man or animal. It is the most effective way to prevent killer diseases or infections especially amongst children between the ages of 0-12 years old. The term vaccination is usually used synonymously or interchangeably with immunization.However, immunization is generally the procedure of making a person immune to a particular infectious disease or pathogen. Immunization can be achieved through several processes which include but not limited to:

  • Passive immunization – which is acquired by a newborn from the mother on birth before the baby starts developing or building its own active immunity.
  • Injecting an antiserum or vaccine into the body.
  • Oral administration of vaccines in tablet or fluid forms.
  • Direct inoculation of a weakened or live organism into the body (this method is archaic, and it is not practiced again). This is known as variolation.

Generally, vaccines are pathogen-imposters – since they act as the carbon copy of the actual pathogen in vivo, thereby stimulating the host’s immune system to produce potent antibodies and other immune system molecules against the invading pathogen in advance. Vaccines prepare and stimulate the body’s immune system to fight against invading infectious disease agents in advance.   According to the World Health Organization (WHO), the widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles and tetanus from most parts of the world. Today, many infectious diseases of man including but not limited to measles and smallpox have been eradicated, and some like polio or poliomyelitis (caused by polio virus) is almost at the verge of complete eradication from the world due to intensive vaccination/immunization programme around the globe.

Vaccination therefore has significantly contributed to the prevention and control of many human infections and diseases. It is noteworthy that the concept of using microbes (as vaccines) especially in their attenuated/weakened forms to treat microbial diseases in humans was first established and conceptualized by Louis Pasteur. Louis Pasteur was the first to develop a potent human vaccine (rabies vaccine in particular) in 1881. Pasteur’s work showed that pathogens can be isolated, inactivated and administered in their weakened or live forms to humans in order to prevent them from acquiring a particular infectious disease. Nevertheless, the field of vaccinology as we know it today was first introduced into clinical medicine by Edward Jenner in 1796 – when he inoculated a 13 year old boy with vaccinia virus obtained from a woman accidentally infected with cowpox. Jenner’s method of vaccination is generally known as inoculation – since it involved the direct introduction of live organisms into the body. However, this practice has become obsolete and is no longer practiced in clinical medicine. It was later discovered by Jenner that the young lad developed immunity to smallpox infection – which caused the death of millions of people worldwide.

The immunity developed in the young man against smallpox disease was due to a challenge with variola (vaccinia) virus which Edward Jenner administered into the boy’s body. Through vaccination and/or immunization, a large population of humans can be protected from becoming infected by an infectious disease or pathogen. This is because, the vaccination of a large human population against a given infection can develop herd immunity in the population – since contacts amongst people in that population will be more with protected and vaccinated individuals instead of with sick and infected persons. Herd immunity helps to reduce the spread and circulation of infectious disease agents within a particular human population. Most of the vaccine-preventable diseases including polio have been significantly reduced and contained in the developing parts of the world. All the vaccines used today for the vaccination and/or immunization of humans are based on the use of killed or live forms of microorganisms or their purified subunits.

Purified antigens of pathogens, toxins and their conjugated protein or polysaccharide molecules can also serve the purpose of vaccination in humans depending on the type of infectious disease they are used to prevent. For human vaccines to be available on a global scale, complex production methods, meticulous quality control measures and reliable distribution channels are needed to ensure that the products are safe, potent and effective for human use. A vaccine can confer active immunity against a specific harmful agent or pathogen by stimulating the immune system to attack the agent. Once stimulated by a vaccine, the antibody producing cells known as B-lymphocytes remain sensitized and ready to respond to the invading pathogen should it ever gain enter into the body of the vaccinated human host in future. Even though no vaccine is entirely safe or completely effective, their use is strongly supported by their benefit to risk ratio. That is, the benefit of using them far outweighs any risk associated to their application in humans. Recently, an experimental vaccine (rVSV-ZEBOV-GP Ebola vaccine) has been developed and approved by WHO for vaccinating or immunizing people in Ebola endemic regions in Africa; and the search for potent vaccines to tackle some dreaded diseases of man such as HIV/AIDS are being steadily pursued with sustained progress and research.

TYPES OF VACCINES

LIVE ATTENUATED VACCINES

Live attenuated vaccines are composed of live, attenuated microorganisms that cause limited or no infection in their host upon administration. The causative agent or microorganism used for the development of live attenuated vaccine is alive but it has lost its natural ability or pathogenicity to cause the disease it is known for. Microbes used for live attenuated vaccines are sufficient enough to induce an immune response but insufficient to cause any infectious disease in the vaccinated individual. Live attenuated vaccines are made by passing the disease-causing virus through a series of cell culture techniques or embryonated chicken egg method (e.g., chicken embryo) under controlled laboratory conditions that make the organism less virulent. Most of the pathogens used for the production of live attenuated vaccines are active viruses that have been cultivated under conditions that disable or inactivate their virulent properties or nature. In some cases, closely related but less dangerous or less-pathogenic microbe can be used to produce immune response in the target individual or human population. Live attenuated vaccines are very efficacious; and they induce a protective form of immunity in the individual being vaccinated. Examples of live attenuated vaccines include: oral polio vaccine, yellow fever vaccine, and MMR vaccine (a combination of measles, mumps and rubella vaccine).

MERITS OF LIVE ATTENUATED VACCINES

  • Very small doses (usually a single dose) are required to induce immunity.
  • Booster doses are not needed for live attenuated vaccines.
  • Antibody formation is very fast within the first seven (7) days of administration of live attenuated vaccines; and the antibodies formed can stay for a long time and can last for a lifetime. This is because, as the virus continues to replicate in its host cell, so will it continue to induce the immune system of the host to produce potent antibodies in advance.

DEMERITS OF LIVE ATTENUATED VACCINES

  • A major concern that must be considered in the use of live attenuated vaccine is the possibility of the virus used for the vaccine development to revert to a virulent form capable of causing disease in the vaccinated individual. Mutations can occur when the vaccine virus replicates in the host (especially in immunocompromised individuals – whose immune system have been weakened), and this may result in a more virulent form or strain of the organism that attacks the host.
  • Since they are live and their activity depends on their viability, the storage conditions for live vaccines must be strictly adhered to. This implies that live vaccines should be maintained at cold chain of temperatures between 2oC – 8 oC at all times during storage. And this increases the cost of production of live vaccines.
  • Administration of live vaccines to immunosuppressed individuals may cause serious illness or even death. And thus their usage is usually restricted in immunocompromised individuals.

KILLED INACTIVATED VACCINES

One alternative to using live organisms in vaccine development is killing or inactivating the microbe. Killed inactivated vaccines are very efficacious like the live attenuated vaccines. The causative agent or microbe used for the development of killed inactivated vaccines is usually inactivated by physical and chemical treatments. Vaccines of this type are generally created by inactivating a pathogen, typically using heat or chemicals such as formaldehyde or formalin as aforementioned; and such chemical and physical treatment makes the organism used for the development of killed inactivated vaccine to be non-pathogenic. This destroys the pathogen’s ability to replicate in a human host. Examples of killed inactivated vaccines include: Inactivated Polio Vaccine (IPV), oral cholera vaccine, rabies vaccine and seasonal influenza vaccine. Toxoid vaccines are also prepared from inactivated toxic compounds of microbes. Some bacterial diseases are not caused by the bacterium itself, but by the toxins that they produce. And for such bacterial diseases or infections, the toxins that the pathogens produce can be used to formulate toxoids or toxoid vaccines for the prevention of infections caused by such toxigenic pathogenic bacteria. A typical example of infections that can be prevented using the toxoid vaccines include tetanus infection caused by the neurotoxins produced by Clostridium tetani.

MERITS OF KILLED INACTIVATED VACCINES

  • Killed inactivated vaccines are safe to use since they cannot revert to a more           virulent form capable of causing disease in the individual being vaccinated or    immunized.
  • They can be administered to immunodeficient persons and pregnant women   because the virus used for the development of killed inactivated vaccine is not          ‘alive’ but killed and inactivated.
  • Killed inactivated vaccines are cheaper than live attenuated vaccines.

DEMERITS OF KILLED INACTIVATED VACCINES

  • Killed inactivated vaccines provide a short length of protection than the live            vaccines.
  • Periodic booster doses are required to maintain long term immunity.
  • Inactivation, such as by formaldehyde in the case of Salk vaccine, may alter the   antigenicity of the vaccine virus. And this might lead to delayed activation of the      host’s immune system upon use.

SUBUNIT VACCINES

Subunit vaccines contain parts or fragments of the target pathogen instead of the whole organisms – as is applicable in live attenuated vaccines and killed inactivated vaccines. They are usually made by isolating a specific protein from a pathogen and presenting it as an antigen on its own. Subunit vaccines generally contain the purified portions of the pathogenic microbe being vaccinated against. The antigenic properties of the pathogen of interest (usually in the form of protein molecules and carbohydrate molecules) isolated in their pure forms are used in the development of subunit vaccines. These isolated purified molecules are expected to stimulate the immune system of the host in advance. Unlike in live attenuated vaccine in which there is possibility of reactivation of the microbe into a pathogenic organism, there is no risk that subunit vaccine (usually known as toxoids) can provoke the disease in the vaccinated individual. One of the major drawbacks in the development of subunit vaccine is the difficulty in identifying potential protective or antigenic molecules (out of the complex protective molecules in pathogens) that could be used as starting materials for the development of the subunit vaccines. Examples of subunit vaccine are Diphtheria toxoid, Tetanus toxoid, Pertussis toxoid and Hepatitis B vaccine.

CONJUGATE VACCINES

Conjugate vaccines (which can also be known as subunit-conjugated vaccines) are developed by linking or joining the polysaccharide component of the causative agent to a protein carrier molecule that augment the immunogenicity and/or antigenicity of the microbe’s polysaccharide molecule when used as a vaccine candidate. Conjugate vaccines are primarily developed against capsulated bacteria (i.e., pathogenic bacteria that forms capsules as a microbial resistant feature). Certain pathogenic bacteria have polysaccharide outer coats that are poorly immunogenic. These polysaccharide outer coats are chemically linked to a carrier protein molecule to form a combination molecule that is antigenic and one that can generate immunity against a given infection in the individual being vaccinated. Examples of conjugate vaccines include Haemophilus influenzae Type B vaccine, Meningococcus A, C, Y, W135 and pneumococcus vaccine.

RECOMBINANT VACCINES

Recombinant vaccines are genetically generated vaccines that are prepared using recombinant DNA technology or genetic engineering techniques. In the preparation of recombinant vaccines, the genes for desired antigens of a pathogenic organism are inserted into a vector (which can be a phage or plasmid) that is inserted into a recipient host for the production of the genes or desired antigens that will be used in the development of the recombinant vaccine. This method is complex and capital intensive. An example of a recombinant vaccine is the Hepatitis B vaccine (HBV) used against Hepatitis B virus (HBV) infection. Hepatitis B surface antigen is produced from a gene transfected into yeast cells (particularly Saccharomyces cerevisiae) and genetically purified for injection into a host.

EDIBLE VACCINES

Edible vaccines are vaccines currently being developed and are prepared by introducing the genes responsible for the antigenic determinant of the virus into crops (especially cereals like maize and rice) that can be eaten or consumed by humans. It is postulated that eating these crops is known to induce some form of immunity in the host. In edible vaccines, the antigenic protein molecule is engineered into an edible plant; and after ingestion, the protein is uncloaked and recognized by the host’s immune system which produces antibodies in advance. Edible vaccine development is still an ongoing process, and it holds the potential in revolutionizing vaccinology in the future.

GENERAL STEPS EMPLOYED IN THE PRODUCTION OF VACCINES

Vaccinology or vaccine production is a multibillion-dollar venture. And it requires a whole lot of manpower, skilled personnel, equipment, and other material and financial resources to see it through. Several clinical and pre-clinical trials of the vaccine developed must also be carried out before the vaccine can finally be certified safe and approved for human or animal use or for other commercial purposes.

The basic steps involved in vaccine production are summarized in this section.

  1. Generation of the antigen: The first step in order to produce a vaccine is generating the antigen that will trigger the immune response in the host organism in advance. For this purpose, the pathogen’s proteins or DNA molecules or the whole pathogen need to be grown and harvested in their pure forms. Some of the techniques used in cultivating the pathogens are explained as follows:
  2. Viruses are grown on primary cell lines from chicken embryo or fertilized eggs or cell lines that reproduce repeatedly. Hepatitis A vaccine and influenza vaccine are generated this way.
  3. Bacteria are grown in bioreactors which are devices that use a particular growth medium that optimizes the production of antigens. Haemophilus influenzae vaccines are produced this way.
  4. Recombinant proteins derived from the pathogen can be generated either in yeast bacteria or cell cultures.
  • Isolation of the antigens: The aim of isolating the antigen from the pathogen is to release as much viral or bacterial particles as possible for the development of the candidate vaccine. To achieve this, the antigen will be separated from the microbial cells used to generate it and isolated from the proteins and other parts of the growth medium that are still present in the bioreactor. After this stage, the isolated molecules are purified prior to further development.
  • Purification: At the purification stage, the antigens isolated are then purified in order to produce a high quality purified product. Purification can be done using different techniques for protein purification such as high performance liquid chromatography (HPLC). Recombinant proteins need many operations involving ultrafiltration and column chromatography for its purification.
  • Addition of other supporting/carrier molecules: This step involves addition of other supporting components to the purified antigenic molecules. The supporting components usually added to the purified protein or microbial substances required for vaccine production include: adjuvants, stabilizers, and preservatives. These substances are added to vaccines being produced in order to boost their activity in vivo as well as preserve them prior to usage.
  • Adjuvants enhance the recipient’s immune response to an antigen.
  • Stabilizers increase the storage life of the vaccines.
  • Preservatives allow the use of multidose vials of a vaccine as required (i.e., it allows a particular vaccine to be used over certain period of time because it contains substances that prevent their spoilage). These substances contained in vaccines, and which prevent their spoilage upon usage or storage is generally known as preservatives. Preservatives allow vaccines to be stored over certain period of time after their initial use.

All the supporting components including vaccine adjuvants, preservatives and stabilizers that constitute the final vaccine candidate are combined and mixed uniformly in a single vial or syringe that can be administered to humans or animals for the prevention of a particular infectious disease.

  • Vaccine packaging: Once the vaccine candidate is put in the recipient vessel (either a vial or a syringe), it is sealed with sterile stoppers, and thus ready for usage. The vaccine is finally labeled and distributed worldwide after receiving approval from the FDA (Food and Drug Administration) or any other national and/or international body that authorizes and approves the usage and distribution of such medications. Several quality control and quality assurance practices (as part of the good manufacturing practices, GMPs employed in vaccine development) are put in place in the production of vaccines since these molecules are biological substances that interact with the internal organs, cells and tissues of living organisms including humans and animals. The safety, efficacy and quality of every vaccine are thoroughly checked and approved by the relevant health authorities (e.g., US Food and Drug Administration, FDA e.t.c) before they are released for usage by the general public or in clinical medicine or for other commercial purposes.       

EXCIPIENTS USED FOR VACCINE PRODUCTION

Excipients are substances added to drug or vaccine in order to make it into an actual pill or medication for administration. Besides the active vaccine itself, several excipients exist that are incorporated into the vaccine during their development. Excipients confer no actual therapeutic effect; instead they help as carrier molecules in the delivery of the therapeutic components of the vaccine or drug in vivo.These excipients include stabilizers, antibiotics, formaldehyde, aluminium gels or salts and preservatives.

  • Aluminium salts or gels are added as adjuvants. Adjuvants are added to promote or enhance the immune response to the vaccine thereby allowing for a lower vaccine dosage.
  • Antibiotics are also added to some vaccines to prevent the growth of bacteria during the production and storage of the vaccine.
  • Formaldehyde is usually added to inactivate bacterial products for toxoid vaccines. It is also used to inactivate unwanted viruses that might contaminate the vaccine during production.
  • Monosodium glutamate (MSG) and 2- phenoxy ethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged even when exposed to heat, light, acidity or humidity.
  • Thiomersal is an antiseptic and an antifungal agent containing mercury that acts as a preservative in vaccines. It is usually added to the vials and/or phials of vaccine that contains more than one dose. The essence of adding these substances is for no other reason other than to prevent the contamination and growth of potentially harmful microorganisms in the vaccines. But due to the concerns of mercury poisoning, thiomersal is no longer used as a preservative in vaccines especially in childhood vaccines. However, thiomersal is still a component of tetanus shots.

GENERAL GUIDELINES ON VACCINE USAGE

Some of the basic precautions observed in vaccine usage are highlighted in this section. To ensure safety and efficacy of the vaccines being used for vaccination or immunization purposes, it is vital to imbibe these safety measures to avoid any predicament that may arise from vaccine usage.

  • Vaccines should not be administered if a child is sick or has fever.
  • Vaccine mixtures should be properly re-suspended by shaking properly in order to obtain a uniform, homogenous suspension prior to its actual administration into the body of the recipient host, man or animal.
  • Vaccines should not be used if the suspension cannot be re-suspended upon usage.
  • Vaccine vials and syringes should be properly stored in the refrigerator at 2oC – 8oC, and as recommended by the manufacturer.
  • Vaccines should not be frozen. Frozen vaccines should not be used for vaccination or immunization purposes but should be discarded.
  • Vaccine should be brought to room temperature prior to usage. This can be done by rotating the vaccine vial or syringe (containing the vaccine to be administered) in the palm of the hand.
  • Spent and expired vaccine vials should be properly discarded according to the local waste management guidelines. They should be discarded away from the reach of children.

Further reading

Acheson N.H (2011). Fundamentals of Molecular Virology. Second edition. John Wiley and Sons Limited, West Sussex, United Kingdom.

Brian W.J Mahy (2001). A Dictionary of Virology. Third edition. Academic Press, California, USA.

Cann A.J (2011). Principles of Molecular Virology. Fifth edition. Academic Press, San Diego, United States.

Carter J and Saunders V (2013). Virology: Principles and Applications. Second edition. Wiley-Blackwell, New Jersey, United States.

Dimmock N (2015). Introduction to Modern Virology. Seventh edition. Wiley-Blackwell, New Jersey, United States.

Kudesia G and Wreghitt T (2009). Clinical and Diagnostic Virology. Cambridge University Press, New York, USA. 

Marty A.M, Jahrling P.B and Geisbert T.W (2006). Viral hemorrhagic fevers. Clin Lab Med, 26(2):345–386.

Strauss J.H and Straus E.G (2008). Viruses and Human Diseases. 2nd edition. Elsevier Academic Press Publications, Oxford, UK.

Zuckerman A.J, Banatvala J.E, Schoub B.D, Grifiths P.D and Mortimer P (2009). Principles and Practice of Clinical Virology. Sixth edition. John Wiley and Sons Ltd Publication, UK.

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