Strategies for vaccine development: an overview


Strategies for vaccine development: an overview

29 Oct, 2020

A vaccine is an immunization strategy against pathogens or their toxins, administered in order to prevent one or more infectious diseases through the exposure of the immune system to their components, in some cases even pathogens attenuated by their ability to cause disease, and the consequent acquisition of the so-called “specific immunity”, especially through the production of soluble antibodies capable of recognizing the pathogen before it comes into contact with the host’s cells.

Vaccines are divided into two broad categories: preventive (or prophylactic) vaccines and therapeutic vaccines, administered to people already infected to enhance their immune response and still the subject of experimental research.

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In this short article, as “vaccines” we will refer exclusively to the first category of preventive vaccines.

The importance of preventive (prophylactic) immunization against infectious diseases is evidenced by the success of global vaccination programs, which have led to the almost total eradication of many diseases in more developed countries.

In COVID-19 emergency, the scientific community immediately activated for the preparation of one or more safe and effective vaccines, at least partially, to prevent SARS-CoV-2 infection and the possible clinical evolution in severe respiratory disease known as COVID-19.

Waiting for the arrival of an effective vaccine, we propose a brief summary of the main vaccine approaches tested so far.

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The origin of vaccine administration

Ancient peoples had already realized that some diseases affected an individual only once in a lifetime; if they managed to overcome the infection unscathed, the subject would no longer get sick with the same disease, or would eventually have incurred clinically milder forms.

For example, various sources report the implementation, in some Asian regions, of prophylactic practices consisting in the inhalation of dust obtained from skin lesions caused by smallpox.

The treated subjects developed an attenuated form of smallpox and above all, in case of further contact with the virus, they would no longer get sick.

The large-scale diffusion of this technique, called variolation, was not possible for several reasons, mainly due to the risk of manifesting, after treatment, not an attenuated form of smallpox, but the disease in all its severity.

The introduction of the first vaccination (and the first vaccine) in history is due to the English doctor Edward Jenner (1749-1823). He noted that cattle ranchers who had contracted cowpox (a disease with a much more benign course) tended not to get human smallpox.

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"Edward Jenner, vaccinating his young child, held by Mrs Jenn". Colored engraving by C. Manigaud after E Hamman, Wellcome Library, London


From this observation the idea was born of vaccinating subjects no longer with material from human smallpox pustules, but with material obtained from similar lesions of cow smallpox.

Because of the role of cowpox in the procedure, Jenner called it vaccination, and the vaccine was defined as the preparation capable of inducing acquired immunity, that is, the ability of the immune system to remember the first milder infection and to fight against a more aggressive infection.

The definitive demonstration of efficacy was obtained by inoculating (several times) the contents of the human smallpox pustules to the vaccinated subjects and observing that they did not develop disease.

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How are vaccines classified?

Once administered, the vaccines simulate the first contact with the infectious agent, evoking an immune response similar to that generated by natural infection, without causing the disease and its complications. The principle behind this mechanism is immunological memory, i.e. the ability of the immune system to remember which foreign microorganisms have attacked our body in the past and to respond quickly by producing antibodies against them.

The distinction between vaccines is linked to the way in which the components capable of triggering the immune response are obtained and produced. Based on the type of active component, vaccines are divided into:

Live attenuated vaccines

They are produced from intact organisms (bacteria or viruses), rendered non-pathogenic thanks to repeated in vitro passages on target cells that reduce their ability to cause disease. This preparation allows the virus to replicate in the vaccinated patient by stimulating his immune defenses, but without causing clinical manifestations. Attenuated virus vaccines include measles, smallpox and yellow fever vaccines.

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Inactivated vaccines

They are produced from microorganisms treated with chemical (acetone, phenol...) or physical (heat and UV rays) means that destroy their ability to replicate in target cells, but maintain the ability to induce an immune response. The most important inactivated vaccines include the vaccine against rabies and hepatitis A.

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Vaccines with purified antigens

They are produced through refined purification techniques, which allow to isolate the specific components – called antigens – of microorganisms, recognized by the immune system. Some examples of these vaccines are the ones against pertussis, meningococcus and seasonal flu.

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Toxoid vaccines

They are produced starting from anatoxins (or toxoids), i.e. toxins – toxic substances produced and released by some microorganisms – which properly treated with physical or chemical agents, lose their toxicity but maintain the ability to activate the immune defenses of the body. Vaccines of this type are used to combat diseases caused by toxin-producing germs, such as bacteria that cause tetanus (Clostridium tetani) and diphtheria (Corynebacterium diphtheriae).

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Recombinant DNA or RNA vaccines

They involve the use of cells as “machinery” to produce large quantities of the required antigen (i.e. the viral component recognized by the immune system). Once the antigen of interest has been identified, it is possible to isolate its DNA and insert it into cells suitable for producing the antigen in large quantities (for example yeast cells). The cells are grown and then killed to obtain the synthesized antigen which will be extracted and purified before being inoculated.

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The first vaccine of this type created to be approved for humans was the hepatitis B vaccine. In Italy, vaccination against the hepatitis B virus has been made mandatory for all newborns for many years. The results of this strategy, although initially criticized, were instead so positive that other countries subsequently decided to follow it.

In the case of RNA vaccines, the RNA coding for viral antigens is injected directly, which are in turn produced by the cells.


"Reverse vaccinology" vaccines

An Italian pride, in order to identify antigens that are not very visible from the immune response found in infected people, thanks to a laborious protocol developed by the research group of Rino Rappuoli in Siena, a vaccine against meningococcus B (Men B) was produced, until then escaped the conventional techniques used for the development of a vaccine.

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This technique starts from the sequencing of the pathogen’s genome, from the bioinformatic analysis of the same to predict potential antigens (approx. 600 in the case of Men B). Starting from the success against Men B, the technology of inverted genetics to produce vaccines useful for humans has been applied to other pathogens, such as streptococcus B and streptococcus pneumoniae.

Written by

Elisa Vicenzi and Guido Poli
Elisa Vicenzi and Guido Poli

Elisa Vicenzi and Guido Poli are united in life and by the passion for scientific research which began, after their respective degrees in Pharmacy (Vicenzi) and Medicine and Surgery (Poli) at the University of Ferrara, first at the "Mario Negri" Institute for Pharmacological Research in Milan until 1986, then at NIAID, NIH in Bethesda until 1993 where Vicenzi specialized in the study of the molecular virology of HIV, the causative agent of AIDS, while Poli focused on the role of cytokines in regulating the latency and replication of the virus. Back in Italy, in 1994 they founded the AIDS Immunopathogenesis Unit at the newborn DIBIT of the IRCCS San Raffaele in Milan; following the SARS epidemic (2003) Vicenzi specialized in research on emerging viruses and has been promoted to Head of the "Viral Pathogens and Biosecurity" Research Unit. In 2021 the Research Unit was redefined "Viral Pathogenesis and Biosafety" (Vicenzi) while Poli was appointed Head of the "H.I.V. - Human Immunovirology ". To their credit they have hundreds of publications and two books as Publishers dedicated to HIV research methodologies ("Human Retroviruses. Methods and Protocols", 2013 and "HIV Reservoirs. Methods and Protocols", 2022).

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