Therefore, vaccination may have an individual benefit, by protecting each vaccinated person, but it may also have a collective benefit for certain diseases, by reducing the number of people likely to contribute to the spread of a disease and by protecting people who cannot be vaccinated.

There are several types of vaccines, the most common being :

• Attenuated live vaccines consisting of live microorganisms (virus, bacteria) which have been modified to lose their infective potential, while retaining their ability to induce protect in a vaccinated individual;
• Inactivated vaccines and subunit vaccines which do not contain live infectious agents. They may contain either fragments of the infectious agent (its wall or its toxin), or the whole infectious agent, which is inactivated.
• More recently, messenger RNA vaccines have been developed. These consist of a molecule known as ribonucleic acid, manufactured in a laboratory from viral RNA, which enables synthesis of a viral protein in our cells. This protein will induce protection in the vaccinated individual.
• A further category is that of viral vector vaccines, which consist of a safe virus to which the gene of a protein of the virus to be countered has been added. This gene will enable viral protein production which will induce protection in the vaccinated individual.

Adjuvants are used in the composition of inactivated vaccines to boost the immune response against the microbial antigen contained in the vaccine. Preservatives and stabilisers may also be used to ensure vaccine quality.

What is the role of adjuvants ?

Adjuvants are added in the manufacture of inactivated and synthetic vaccines to boost the immune response against the microbial antigen contained in the vaccine. They are used, among other things, to trigger the warning signal, so that the immune system is activated and the vaccine works.
They also make it possible to reduce the quantity of antigen per dose, i.e. reduce the number of doses required to provide good immunisation.
Attenuated live vaccines (such as measles-mumps-rubella) does not need any adjuvant: they are sufficiently immunogenic.

Main adjuvants

Based on all the data available, experts deem aluminium salts to be the adjuvant of choice for boosting the efficacy of vaccines against pathogens requiring high antibody levels for prevention.

Aluminium salts are among the most commonly used adjuvants worldwide with over 90 years of follow-up in respect of their use, and hundreds of millions of injected doses.
Novel adjuvants for novel vaccines have been developed, particularly emulsions and phospholipids. Others are under development.
Calcium phosphate-based adjuvants were developed in the 1970s, but were subsequently abandoned. The literature data did not demonstrate either superior tolerance or superior adjuvanticity.

Batch release: two-pronged specific control

Every year in France, approximately 25 million vaccine doses are sold : around twenty vaccines without adjuvants for children and adults (approximately 13.3 million doses administered per year, primarily the flu vaccine), and around thirty vaccines in adjuvants (combined vaccines) for children and adults (approximately 12.4 million doses per year) [source: sales in 2016].

Approximately 350 batches of Northern hemisphere seasonal flu vaccines are released each year in 3 months to cover the start of the vaccination campaign from late September.

Vaccines are sensitive medicines: their production uses starting materials of biological origin, as well as a complex process, subject to variability. Their marketing conditions are enhanced via a release process by a national authority in addition to the quality control generally performed by the manufacturer.
ANSM’s release control for each batch, alongside the quality control performed by the manufacturers, is a further guarantee of vaccine safety.

Guarantee of quality and independence of controls

The concept of batch-by-batch release by an independent authority in parallel with the manufacturer, is an additional guarantee of control over time of the pharmaceutical safety and quality of vaccines.
Vaccines consist of active substances of biological origin. Some production systems involve live organisms (culture on eggs, on cells). The manufacturing processes are often lengthy and complex. Low active substance dosages or low frequency of use also increase the benefit of batch-by-batch monitoring under the responsibility of an authority independent from the manufacturer to ensure quality and ensure production remains regular over time.

ANSM’s laboratories are the leading vaccine release centre in Europe. The Agency releases almost 40% of vaccine batches used in Europe and approximately 50% of vaccine doses administered in France every year. ANSM is also heavily involved in United Nations vaccine programmes (batch release on behalf of the World Health Organization).

Vaccine batch control in brief

Controls are performed routinely on finished product samples and also on production intermediates.

They primarily consist of testing the following parameters:

• Identification ;
• In vitro / in vivo activity ;
• Stability ;
• Microbiological safety ;
• Physicochemistry ;
• Product characterisation ;
• Specific toxicity.

In practice, around 20 valences* incorporated in over 40 vaccines from 5 different producers are tested by ANSM.

*A valence is the part of a vaccine providing protection against a single microorganism. A multivalent vaccine may provide protection against several microorganisms causing the same disease (such as the 13-valent pneumococcal vaccine) or against different diseases (such as the measles-mumps-rubella vaccine)

Viral vaccines (i.e. those protecting against viral infections)

The main controls are as follows :

• Titrations in cell culture for attenuated live vaccines (measles, mumps, rubella, yellow fever, attenuated polio vaccine) ;
• Radial immunodiffusion (influenza vaccines) ;
• Neurovirulence test (attenuated polio vaccine) ;
• In vitro activity tests primarily using the ELISA method (hep B, hep A, inactivated polio vaccine, rabies).

Bacterial vaccines (i.e. those protecting against bacterial infections)

The main controls are as follows :

• Bacterial culture (BCG) ;
• In vivo activity tests (Diphtheria, Tetanus, Acellular or Whole Cell Pertussis) ;
• In vitro toxicity, identification and production monitoring tests (Tetanus, Diphtheria, Pertussis) ;
• Physicochemical methods: polysaccharide quantification using chromatographic, colorimetric, nephelometric methods. Polysaccharide molecular size distribution using high-performance liquid chromatography.

Post-marketing vaccine surveillance

ANSM monitors the safety of use of vaccines in general, particularly by monitoring adverse reaction reports (pharmacovigilance) and conducting pharmaco-epidemiological studies. We update healthcare professionals and the general public regularly on the results of this monitoring.

Vaccines containing mandatory valences for children: an enhanced surveillance framework

This surveillance framework, coordinated by ANSM, consists of proactively raising awareness among healthcare professionals and the general public of adverse reaction reporting. The methods envisaged by ANSM for optimised enhanced surveillance include :

• Assistance with report input specifically for vaccines on the reporting portal in addition to indicator and alert threshold tracking based on the reports compiled via the portal ;
• Implementation of statistical signal detection on the French national pharmacovigilance database (BNPV) ;
• Implementation of tracking indicators of cases of adverse reactions recorded in the French national pharmacovigilance database (BNPV) tailored to each of the vaccines in question.

Besides pharmacovigilance activities, ANSM will use information from the French national health data system (SNDS) to track the incidence of post-vaccination adverse reactions identifiable form hospital admission data.
If necessary, additional pharmaco-epidemiological studies may be conducted.

Vaccine availability

Vaccines are considered as medicines of major therapeutic value (referred to as MITM). For this reason, ANSM is involved in managing shortages and supply tensions in respect of these medicines, collaborating closely with all of the pharmaceutical companies concerned.

There are multiple possible causes of vaccine supply tensions and stock shortages: substantial increase in global demand, problems arising during productions liable to impact vaccines before or after they are supplied to the market.

The vaccine manufacturing process is complex and longer (from 6 to 22 months) than for other medicines. This explains why the process to restock products may be lengthy and gradual.

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