Vaccines are biological medicines aimed at preventing one or more infectious diseases by stimulating the immune system (production of antibodies, activation of specific cells) and the consequent acquisition of the so-called "active immunity".

The "active substances" of vaccines consist of:

• micro-organisms (bacteria or viruses) suitably inactivated or killed so as to stimulate the immune system without causing the disease;
• specific parts (antigens) of micro-organisms which are directly involved in the response of the immune system to such pathogen;
• substances produced by the micro-organism itself (toxins) and involved in the mechanism whereby the pathogen causes the disease; such substances are made harmless and effective through the vaccine production process.

In some vaccines, such active components are produced from micro-organisms other than the one causing the disease, by means of specific biotechnologies.

In addition to the active components, some vaccines contain "adjuvant" substances, which facilitate a relevant response of the immune system with lower amounts of antigen.

Furthermore, some formulations provide preservatives and/or stabilizing substances which are necessary to maintain the chemical, physical and biological characteristics of the products. Finally, traces may be present of substances used in the vaccine production process, such as egg proteins or substances used to inactivate some viruses and bacterial toxins.

The quantities of adjuvant substances, preservatives and stabilizers contained in the vaccines, as well as residual traces of processing must be within the limits laid down by the law.

Vaccines are primary prevention strategies for infectious diseases and are administered in subjects at risk of exposure to a specific micro-organism before such exposure occurs, in order to prevent outbreak of the disease.

Some vaccines, such as those for tetanus or rabies, are also used as a secondary prevention strategy to limit severity of the disease, i.e. after contact with the pathogen (post-exposure prophylaxis). However, this is an emergency procedure and does not replace primary vaccination, which represents the first-choice strategy.

Other vaccines are used as a form of prevention against some types of infectious cancer. Some examples of this typology include anti-hepatitis B virus and anti-human papillomavirus vaccinations, used respectively for prevention of liver cancer due to chronic hepatitis B virus and for prevention of cervical and anal cancers.

In recent years, in addition to the classic type of "prophylactic" vaccine, "therapeutic" vaccines are also being studied in subjects with specific diseases, especially in the field of oncology, which prove promising in stimulating the patient's immune responses against cancer.

In general terms, vaccines induce an immune system response of the vaccinated person (immunization) similar to that caused by natural infection or more generally by contact with the virus or the bacterium present in nature, without triggering the mechanisms leading to signs and symptoms of the natural disease.

Immunization and, namely, active immunity, is the process whereby our immune system learns about micro-organisms and responds quickly and effectively to neutralize their harmful effects. It is a complex event due to the interaction between the pathogen and the immune system cells, which can occur either following infection/contact with the "wild" micro-organism or following a vaccination.

The immune system is made up of a complex set of circulating cells (white blood cells) and organs (bone marrow, lymph nodes, spleen) that in general terms acts as a defense of our body. The main task of the immune system is to recognize as self anything belonging to the organism and as non-self/foreign the cells of other organisms, so as to be able to defend itself, if necessary.

The cells involved in the development of the acquired immunity induced by the vaccine or by the disease are basically those with a phagocytic action (macrophages, dendritic cells) and lymphocytes. The latter are in turn distinguished in type B lymphocytes, capable of producing antibodies (humoral immunity), and type T lymphocytes, which intervene directly or indirectly on the infected cells (cell-mediated immunity).

A part of the activated lymphocytes is transformed into memory cells and can persist over time in order to face a subsequent attack by the micro-organism. This very mechanism of selection and maintenance of memory cells for each specific micro-organism (immunological memory) underlies the effectiveness of vaccination and determines the ability of the immune system to remember which foreign micro-organisms have come into contact with the organism in the past, so as to be able to respond quickly. Without vaccinations, the human body can in fact require up to two weeks to produce enough antibodies to counteract the micro-organism in question.

In order that the above procedure be properly carried out, for some vaccines (mainly inactivated ones) it is necessary to administer boosters, i.e. repeating the administration at a distance of time. The number and frequency of the boosters required depend on the characteristics of both the vaccine and the pathogen.

Vaccines provide various levels of protection, depending on the disease to prevent. For non-communicable human-to-human diseases (for example, tetanus), they guarantee the protection of the vaccinated person (individual protection). For human-to-human communicable diseases (for example, measles), they not only protect the vaccinated person, but also guarantee the protection of the community, by reducing dissemination of communicable diseases within a population.

The infection spreads from person to person when an infected person comes into contact with a susceptible individual. If the number of immune people exceeds a threshold, the transmission stops: this occurs before reaching a 100% vaccination coverage. The percentage of immune individuals within a population over which a disease does not spread is the so-called "herd immunity threshold". This percentage varies depending on a series of factors, including the virulence and transmissibility of a given infectious agent, the efficacy and the overall coverage of the vaccine and the vaccination coverage of the population at risk.

Depending on the type of active component, the vaccines are divided into:

• live attenuated vaccines, produced from non-pathogenic micro-organisms (for example, those containing viruses of measles, rubella, parotitis, varicella, yellow fever and mycobacterium tuberculosis)
• inactivated vaccines, produced from micro-organisms killed through exposure to heat or with specific substances (for example, those containing hepatitis A virus, poliomyelitis virus, and influenza "split" or "fragmented” virus)
• purified antigen vaccines, produced through purification techniques of the bacterium/virus components interacting with the organism (for example, those containing the antigens of the bacteria causing pertussis, meningitis and those containing the antigens of the influenza virus defined as "subunit vaccines")
• anatoxin/toxoid vaccines, produced in most cases from proteins released by the micro-organism (toxins) that may cause the disease (for example, those containing the tetanus and diphtheria bacterial exotoxins)
• recombinant DNA (biotechnological) vaccines, produced starting from the DNA portions of the micro-organisms coding for a specific antigen through a biotechnological procedure (for example, those for hepatitis B and for meningococcus B)

Vaccines can also be differentiated, depending on the active components contained, into single-component or monovalent (one antigen), i.e. vaccines able to prevent a single disease, and into multi-component or multivalent (more antigens), for prevention of more diseases with a single administration.

Finally, vaccines can be classified according to the administration route, into intramuscular, subcutaneous and oral vaccines. Some influenza vaccines are also available in a nasal spray formulation (currently not marketed in Italy).

The development of a vaccine is a rather long and elaborate process starting from knowledge of the micro-organism responsible for the disease aimed to be prevented and its modalities of interaction with the human body. Initially, in vitro experimental studies are carried out, on the basis of which it is possible to establish the ideal qualitative and quantitative composition of a vaccine (type and quantity of the active component and of all the other substances envisaged).

Once this aspect has been defined, the potential vaccine is submitted to pre-clinical trials which include in vitro and animal model studies, defining the mechanism of action (i.e. the ability to trigger the immune response), the toxicological profile and the first evidence of efficacy and safety on a complex living organism.

This phase makes it possible to select the formulation which proves more promising in the experimental designs: such formulation will later be sent to the preliminary clinical phase on humans. As for multicomponent vaccines, in this phase it is necessary that the possible interference be also studied between the various active components of the vaccine.

At this stage, the vaccine undergoes the clinical trial pathway, which can be carried out in four phases: the first three precede the marketing authorization and the fourth is performed when the vaccine is already available on the market.

During the first three phases, the population treated with the vaccine is progressively increased, the dosage is defined (i.e. number of doses for primary immunization and booster ‑ if applicable), the efficacy of the vaccine or immunogenicity is characterized (i.e. the ability to stimulate a human specific and sufficient antibody response against the vaccine components) as well as its safety or reactogenicity (i.e. the type and frequency of any adverse reactions). The last two issues are especially investigated in Phase III clinical trials, which are performed on very large populations of subjects to whom the vaccine is aimed.

In these studies, efficacy is confirmed (in terms of type and persistence of the immune response, percentage of subjects who effectively respond to the vaccine and, when possible, reduction of the probability of developing the disease after vaccination) as well as the safety of the vaccine (in terms of adverse events attributable and not attributable to the vaccine and of possible problems related to the characteristics of the subjects such as age, sex and specific health conditions).

Furthermore, in these three phases the possibility is explored of administering the vaccine under development, together with other vaccines already on the market, to particular categories of subjects, in order to obtain specific information on possible interferences in terms of efficacy and safety.

Phase III clinical trials are:

• controlled, since the subjects treated with the vaccine under study are compared with as many subjects treated with a similar vaccine already authorized or with an inert treatment (placebo);
• randomized, since the division of the subjects into either treatment occurs randomly.

This type of study represents the most solid scientific tool to demonstrate the efficacy and safety of a medicinal product, including vaccines, as it allows to attribute with reasonable certainty the differences observed in the subjects involved in the study exclusively to the medicine/vaccine.

Phase IV clinical trials (or post-authorization studies) are carried out post-marketing and aim to verify the efficacy and safety of the vaccine in its real conditions of use, to evaluate its use in particular population subgroups and pathological conditions (for example, in the course of immune system diseases which could change the efficacy and safety of the vaccine) and the cost-benefit ratio related to the disease and/or to other vaccines.

All the development phases of a vaccine are necessary to obtain the clearest and most comprehensive information possible on indications, contraindications, special warnings, benefits and risks of the product. Since vaccines are administered as a preventive measure in a healthy population, it is necessary that the percentages of efficacy are very high (number of subjects adequately responding to the vaccine) and that the benefit is far greater than the risk.

Therefore, any time throughout this process, the development of the vaccine or its marketing can be interrupted if just one of such fundamental conditions is not met.

All the studies performed in the development of a vaccine (as for all medicines) must comply with the international standards of ethics and scientific quality established by the provisions of good clinical practice (GCP), which are codified worldwide.

In the European Union vaccines are authorized on the basis of quality, safety and efficacy requirements defined by European and international guidelines for all medicines, taking into account the specific characteristics of these products.

The scientific data submitted by the pharmaceutical companies are subjected to a scrupulous technical and regulatory evaluation ending with either a positive opinion (leading to approval) or a negative one (non-approval) on the relationship between the benefits and risks associated with the use of the vaccine in human beings.

From a regulatory point of view there are two procedures: the Community and the National procedures. The Community procedure can be centralized (with the involvement of all EU Member States coordinated by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), pursuant to Reg. 726/2004), or of mutual recognition and decentralized (whereby a Member State acts as Reference Member State, pursuant to Legislative Decree 219/2006). A National procedure occurs when the authorization involves only one country (Legislative Decree 219/2006).

Biotechnological vaccines (for example, recombinant DNA vaccines) can only be authorized through a centralized procedure (EMA).

In any case, any vaccine and medicinal product must be granted a Marketing Authorization (MA) from AIFA before they can be marketed in Italy.

Influenza vaccines available in Italy are authorised by AIFA and/or EMA.

Their composition is updated each year according to the indications of the World Health Organisation (WHO), on the basis of epidemiological and virological information collected by a global network, active throughout the year, consisting of 140 collaboration centres.

This allows not only to monitor the overall trend of the transmission of influenza but also to identify the circulating strains and to select those to be included in the composition of the vaccines.

The antigenic characteristics of viral strains that circulated in the last flu season provide the basis for selecting the strains to be included in the following year’s vaccine.

WHO recommendations on vaccine composition are generally disseminated in February to allow companies to produce the required amount of vaccine.

Subsequently, the companies submit to AIFA and/or the EMA the procedures for updating the composition of influenza vaccines that are approved by the summer. Every year, before the beginning of the flu vaccination season, the AIFA Determination that authorises the update is published in the Official Journal and on the institutional portal. The list of vaccines authorised through European procedure is also published on the website.

All influenza vaccines authorised in Italy are listed in this document.

The Vaccine Schedule, included in the National Vaccine Prevention Plan 2017-2019, provides for the free and active dispensation by the National Health Service of influenza vaccination for people over the age of 64 and belonging to particular categories at risk.

AIFA follows all stages of quality control, safety and effectiveness of the vaccines starting from the development phase and from the assessment of the dossier provided during the authorization phase, up to the inspections of the production plants, by checking the implementation of good manufacturing standards and controlling each batch before marketing. The authorization dossier contains all the quality data relating to the raw materials used and the production process, as well as all the results of non-clinical and clinical trials, including authorization certificates.

The production process of a vaccine, like all medicines, must comply with Good Manufacturing Practices (GMP) which guarantee its high quality and reproducibility.

AIFA periodically carries out inspections - even without notice - at the plants and premises authorized for production, control and storage of all medicines, including vaccines, both in Italy and outside Europe. During inspections in facilities producing immunological medicines, AIFA verifies that the production processes are duly validated to continuously guarantee compliance of the batches with the specifications authorized in the registration dossier.

Experts from the National Institute of Health (ISS) take part in the inspections concerning production of immunological medicines. Vaccine production facilities located in other EU countries are regularly inspected by the competent local authorities, according to standards shared at European level (EU-GMP). In the case of vaccines authorized through centralized procedure, facilities located in non-EU countries are subject to inspections coordinated by the European Medicines Agency (EMA).

If the inspection ascertains that the manufacturer complies with legal obligations and with the principles of GMP guidelines, AIFA issues the relevant certificate of conformity.

The controls are carried out throughout the vaccine production cycle and before each batch is marketed, according to the standards provided by international (WHO, EMA, etc.) and national authorities. The supervisions are performed by both the manufacturing company and by an international network of accredited laboratories, certified and in turn controlled by other bodies, regardless of the country where a single batch of vaccine is distributed (state control).

The adequacy of vaccine production and the possible presence of contaminants due to the production process are verified twice on each batch before it is delivered to the vaccination centers. For batches that successfully pass these checks, AIFA issues a batch release certificate, which allows them to be marketed, whereas those not complying with the established standards are not placed on the market.

The supervision activity on the quality of vaccines and of all the medicines available on the market is carried out also through managing reports related to the possible presence of defects in one or more batches of medicines or raw materials. The defects reported are divided into three classes, according to their severity and dangerousness, and if the ascertained defect represents a serious health risk, restrictive measures are laid down.

Specifically, AIFA may prohibit the sale and use of vaccines and medicines in general and order withdrawal from the market of one or more batches or of the entire product (Article 142 of Legislative Decree 219/2006) .

Moreover, AIFA performs pharmacovigilance inspections - even without notice - at the companies’ pharmacovigilance offices and departments, with an aim to assess that companies comply with Italian legislation, EU legislation and Good Pharmacovigilance Practices (GVP) (Ministerial Decree of 30 April 2015).

A further tool is the annual control program of the composition of the medicines marketed in Italy ‑ performed every year through AIFA Resolutions, upon receipt of the ISS (National Institute of Health) opinion - which provides for drafting a list of medicinal products, including vaccines, and active substances to be sampled and analyzed in order to verify compliance with the quality specifications authorized and reported in the registration dossier and/or in the European Pharmacopoeia monographs.

If the analytical results show differences with respect to the authorized specifications and if the opinions of the ISS are not favorable, AIFA shall prohibit their sale and use and order withdrawal from the market.

AIFA is the competent authority in Italy for monitoring the safety of vaccines (and in general, of all authorized medicinal products) during the entire life cycle of each individual product (vaccine vigilance). This activity is essentially based on the analysis of suspected adverse reactions reports, collected through the National Pharmacovigilance Network and the European pharmacovigilance system EudraVigilance. Another database used for the surveillance of vaccines and medicines in general is the VigiBase system of the World Health Organization (WHO).

These databases are interconnected in such a way that the suspected adverse reactions reported at a national level can provide the European and global system with more extensive data than those collectable from a single population. It is worth highlighting that the activity performed at a national level is in fact integrated into a wider surveillance system at both a European level (in collaboration with the other EU National Competent Agencies) and a global level.

The analysis of suspected adverse reactions reports consists in the evaluation of all the events occurring after administration of a vaccine, in order to highlight possible associations between the administered product and the event which has occurred.

Suspected adverse reactions reported during clinical trials prior to authorization of the vaccine are considered in the assessment of the marketing authorization application: the goal is to define the benefit-risk ratio of a product. The outcome of this evaluation is fundamental not only to define the contraindications, warnings and adverse reactions to be reported in the Summary of Product Characteristics (SPC) and in the Package Leaflet (PL), but also to proactively outline all the monitoring activities of the vaccine safety to be conducted after marketing, as part of a risk management plan (RMP).

Both the product information and the RMP can be modified any time after marketing, based on the evidence inferable from further clinical studies performed after the authorization (phase IV) or from pharmacovigilance activities carried out by both the Marketing Authorization Holder and the competent regulatory authorities.

The MAHs are legally bound to regularly submit a Periodic Safety Update Report (PSUR) which shall be evaluated by the EU regulatory agencies. Regulatory authorities such as AIFA or EMA, instead, systematically monitor suspected adverse reactions reports through signal analysis activities and can at any time request a re-evaluation of the safety of a vaccine or any medicine through specific procedures at a European level.

In this way it is possible to constantly update the benefit/risk ratio of each vaccine and adopt the appropriate safety measures, whenever the post-marketing surveillance activity detects significant information on any adverse reactions already or not yet known.

The vaccine vigilance activity in Italy is carried out by a specific AIFA working group, with the participation of the ISS, the Regional Pharmacovigilance Centers, the Ministry of Health and the regional contact points on prevention.

The assessment of the correlation between an adverse event and a vaccine includes:

• collection of all the data available in the National Pharmacovigilance Network;
• integration with clinical and non-clinical data in literature;
• assessment of the probability that the vaccine may have caused the event in the individual case (causation);
• validation of the signal performed first at national level and then at European level by the EMA Pharmacovigilance Risk Assessment Committee (PRAC).

If the signal has a significant impact on the benefit-risk ratio, for example due to severity or frequency, the individual Member State raising the signal or the PRAC may decide to assess the possible risk through other procedures.

In any case, the PRAC evaluates all data available (those provided by companies or available in national, European and WHO pharmacovigilance databases) and the scientific evidence published in literature, with an aim to establish a possible correlation and to assess the clarity of such correlation.

The recommendations provided by the PRAC are also submitted to the scrutiny of other EMA committees, who may use the opinion of a specially convened committee of experts and shall finally be approved by the European Commission. Such recommendations are periodically published on the EMA website, thus made available to any stakeholder involved, and communicated by the individual national regulatory authorities.

All the safety evaluations and the related decisions able to modify the information on a vaccine are based on a precautionary principle, whereby the risk value is also attributed to factors and events not yet clearly defined.

An adverse event that is potentially or clearly related to the use of the vaccine must be reported in the product information (SPC and PL), in the sections relating to adverse reactions and/or in the sections relating to warnings or contraindications and may involve a variation of the risk management plan.

Serious or very frequent adverse events can alter the benefit/risk ratio of a vaccine so that the regulatory authority, pending further investigation, may suspend or even revoke the marketing authorization and order withdrawal from the market.