Vaccination involves protecting an individual against a disease by stimulating their immune system. Preventive vaccines prevent the onset of an infectious disease. Therapeutic vaccines help patients to fight an existing disease, for instance, cancer. Vaccine research aims not only to develop new vaccines, but also to improve the comfort, tolerability and efficacy of existing vaccines.
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Understanding vaccines and vaccination
According to the World Health Organization, vaccination saves the lives of 2 million people each year worldwide. International campaigns have led to the eradication of smallpox, a 99% reduction in cases of polio between 1988 and 2003, and a 40% reduction in cases of measles between 1999 and 2003. In France, thanks to the vaccine, the incidence of mumps fell from 859 to 9 cases per 100,000 inhabitants between 1986 and 2013.
However, a number of diseases are still rampant throughout the world even though vaccines exist: There has been a resurgence in whooping cough in the United States, particularly in California, since 2011. Rubella has been rife in Eastern Europe, particularly in Poland and Romania, since 2012. Between 2008 and 2013, measles has risen in force in Western Europe, particularly in Germany and Eastern France. Only maintaining a good level of vaccine coverage, i.e., a high rate of immunized individuals in the population, can keep these diseases at bay.
Vaccination is beneficial from an individual perspective (due to protecting each immunized individual) and from a collective perspective (due to reducing the number of persons liable to contribute to the spread of a disease). It is of interest in terms of public health (due to avoiding complications related to the diseases concerned), but also from an economic perspective (due to reducing healthcare consumption, hospital admissions, disability and even sick leave from work, etc.).
Each year, the Haut conseil de la santé publique updates the vaccine schedule. It defines the vaccinations and boosters to be performed according to age, for the general population and in special cases (immunosuppressed individuals, pregnant women, foreign travel).
How does a preventive vaccine work?
Preventive vaccination involves administering an attenuated or inactivated form of an infectious agent (or some of its constituents) to a healthy individual. The objective is to trigger an immune response enabling subsequent contamination to be avoided. Vaccination allows the development of "memory" immune cells, able to immediately recognize the pathogenic agent if it were to subsequently infect the individual.
Vaccination. How does it work?
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After administration of the vaccine, the attenuated/inactivated microorganism or its constituents (microbial antigens) are captured by immune system cells, antigen-presenting cells, directly at the injection site. These cells then migrate to the nearest lymph node to present the antigens to the CD4 T-lymphocytes. Over the next few hours, the latter activate the CD8 killer T-lymphocytes and the antibody-producing B-lymphocytes. These cells are able specifically to eliminate the microbial antigens within 3 to 5 days. Furthermore, a few memory T and B-lymphocytes and specific antibodies persist in the body for several years: these protect against possible future infection with the same pathogen.
Therapeutic vaccine, or immunotherapy
Therapeutic vaccines are not intended to protect individuals against infection, but to help them fight disease by stimulating their immune system. This method involves injecting a factor able to unlock the immune system blocked by the mechanisms of the disease. This factor may be: microbial or tumoral antigens, modified immune cells or molecules facilitating the task of the immune system.
This therapeutic approach has become incredibly popular in oncology, with promising results. Trials are also being conducted in infectious diseases, notably to fight against chronic HIV infection. In this case, the goal is to maintain a sustainable patient viral load at the lowest level possible, by stimulating their immune system against cells which host the virus.
What does the vaccine contain?
Although vaccines have long been designed in an empirical manner, advances in cellular and molecular biology now make it possible to identify the subunits of infectious agents comprising sufficient elements to induce an immune system response. Owing to this new knowledge, it is now possible to improve efficacy while limiting the side effects of vaccines.
Major vaccine classes
- Live attenuated vaccines contain live pathogenic agents, the virulence of which has been attenuated by culturing under special conditions (exposed to cold, for instance). These vaccines induce an infection with little or no symptoms. This is the case for vaccines against tuberculosis (BCG), chickenpox or, even the trio, measles-mumps-rubella (MMR). These vaccines offer long-term protection after one or two injections. They have excellent immunogenicity, i.e., potential to induce an immune response, similar to that of the virulent pathogen. Nevertheless, there is still a risk of infection due to these vaccines. Hence, they must not be administered to individuals with an immunodeficiency or to pregnant women. Furthermore, it is not always possible to attenuate the virulence of a microorganism while preserving its immunogenic properties: this principle cannot therefore be proposed for all infectious agents for which vaccine development is desirable.
Immunosuppressed individuals have a deficient immune system, which can sometimes be severe, owing to hereditary or acquired diseases (HIV, leukemia, etc.), or due to immunosuppressant therapy (after transplantation, for example). The use of live vaccines is contraindicated in this specific situation, as they are liable to cause infectious disease associated with the vaccine. Special vaccine regimens may be necessary for other types of vaccines to compensate for the decreased immunogenicity of the vaccines owing to immune deficiency. The health status of these individuals can also warrant specific vaccination, particularly against invasive pneumococcal infections or seasonal influenza.
- Inactivated vaccines contain whole microorganisms which have been killed by heat or chemical treatments. This is the case for a polio vaccine administered by injection. These vaccines do not therefore present any risk of infection; however, they often cause substantial reactions (pain, redness and swelling at the injection site, fever, and muscle/joint pain).
- Subunit vaccines contain the necessary and sufficient fragments of purified microorganisms, to train the immune system to recognize the whole microorganism. This is the case for pneumococcal, meningococcal and even whooping cough vaccines. Other subunit vaccines contain bacterial toxins, having undergone heat or chemical treatment so that they are no longer toxic (toxoids). This is the case for tetanus and diphtheria vaccines. Subunit vaccines do not present any risk of infection and are better tolerated than inactivated vaccines. However, their ability to induce an immune response can be weak (vaccines with limited immunogenicity). Several injections and boosters are thus required for long-term immunization, together with the addition of adjuvants to enhance the induced immune response.
- Lastly, certain vaccines are produced genetic engineering. These do not directly result from the isolation and purification of an infectious agent or one of its constituents: the antigen is produced from a gene of the microorganism which is expressed in cultured cells.
Monovalent, multivalent and combined vaccines
Monovalent and polyvalent vaccines exist. The first provide immunization against a single pathogenic agent, whereas the second offer immunization against several sub-types of a given virus or bacterium. This concerns, for example, for the Prevenar 13® and Pneumo 23® vaccines against pneumococcal infections, which contain antigens of several pneumococcal sub-types, providing immunization against 13 and 23 different serotypes, respectively.
Combination vaccines also exist, containing antigens of several different infectious agents. For example, the MMR vaccine offers protection against measles, mumps and rubella.
And what else?
In addition to the microbial antigen(s) constituting the active substance, a vaccine contains:
- Stabilizers which guarantee the durable quality of the vaccine after production. These prevent degradation of the pathogenic agent or its fragments, and prevent them from adhering to the walls of the vial, etc. These usually consist of sugars (lactose, sucrose), amino acids (glycine) or proteins (albumin, gelatin).
- Preservatives which prevent any bacterial or fungal proliferation.
- A diluent, usually water or a sterile saline solution, to dilute the vaccine before administration.
- And, in the majority of cases, except for live attenuated vaccines, an adjuvant used to increase the immune response to the microbial antigen.
Role of the adjuvant
There are two types of immune response. An "innate" response, which is local and rapid, but not specific to the infectious agent to be eliminated. The second type of response, dependent on activation of the first, occurs more slowly. However, it is more effective and, above all, specific to the "identified" pathogen. Vaccination seeks to achieve this second form of immunity, known as adaptive or specific immunity. This is the only type of immunity to yield immune cells which memorize the pathogenic agent for several years.
Adjuvants stimulate the innate immune response required in order to activate the specific response essential to successful vaccination. Live vaccines are highly immunogenic and do not require an adjuvant. However, the majority of other vaccines do not induce a sufficient innate response, hence the need for an adjuvant. Adjuvants also make it possible to limit the antigen doses to be administered, reduce the number of injections necessary for adequate immunization, and strengthen the immune response in individuals with a weak response (immunosuppressed or elderly subjects, etc.).
In France, 26 vaccines (corresponding to 13 million doses administered in 2012) do not contain an adjuvant, whereas an adjuvant is found in 30 vaccines (10 million doses in 2012).
The adjuvants most widely used, given the extensive data in favor of their safety, are aluminum salts. New adjuvants have also emerged since the 1990s: squalene (steroid precursor), bacterial derivatives and even artificial vesicles made up of lipids, with or without viral proteins (liposomes and virosomes). These have been developed for situations in which aluminum is ineffective (for instance, in the influenza vaccine) or to boost the effect of aluminum (for instance, in an anti-HPV vaccine).
Questions surrounding the aluminum adjuvant
Misgivings regarding vaccination are based on the presence of an adjuvant containing aluminum salts in certain vaccines. Used since the 1920s, these salts have been associated with extremely rare cases of macrophagic myofasciitis in adults, a disorder characterized by muscle lesions associated with the infiltration of aluminum-impregnated macrophages. Individuals with these lesions can experience pain, weakness, fatigue, and neurological disorders.
Approximately 500 cases of macrophagic myofasciitis were recognized by the Nancy reference center between 2002 and 2013 in France. The causes of this disorder are unclear, and researchers suspect there may be a genetic predisposition which could prevent the natural elimination of aluminum in affected individuals. The French National Agency for Medicines and Health Products Safety (Ansm) is attempting to clarify this association: in 2013, it awarded funding to an Inserm team to study the pathway and fate of aluminum in the body, together with the impact of these salts on animal models and in humans.
Why have a vaccination?
Individual, but also collective benefit
The spread of a contagious disease in a population is directly related to the proportion of subjects liable to contract the disease: hence, the greater the number of people vaccinated, the lower the risk of transmission. When this number is very high, the immunized population form a barrier between contagious individuals and non-immunized individuals. The pathogen then ceases to circulate in the population. This group protection therefore protects vaccinated individuals, but also non-vaccinated individuals.
This strategy has already led to smallpox being wiped out in France and worldwide. It, moreover, makes it possible to limit the spread of numerous other microorganisms and could lead to other diseases being eliminated, such as measles and hepatitis B. The WHO has devised an action plan on this subject.
Importance of vaccine coverage goals: the case of measles and diphtheria
In France, more than 23,000 cases of measles were recorded between 2008 and 2012 (in three epidemics), resulting in over 1,000 cases of serious lung disease, 30 cases of neurological complications (encephalitis or myelitis), and 10 deaths. At least 95% of the population would need to have received 2 doses of the vaccine at the age of 24 months in order to eliminate measles. Although vaccine coverage is constantly increasing, and has now reached 90%, this is still not enough. The very large majority of individuals contaminated in recent epidemics had not been vaccinated (80% of cases), or had been inadequately vaccinated (only 1 dose of vaccine). Nevertheless, 5% had received the two doses recommended by the vaccine schedule and had probably therefore responded poorly to the vaccine. They would probably have been protected if optimum vaccine coverage had been achieved, preventing the virus from circulating.
As regards diphtheria, this disease is practically no longer a part of the European landscape, after its devastating effects on children in the 19th century. However, it is still rife elsewhere, causing epidemics in certain countries, such as Algeria, the former USSR, and even Thailand in the 1990s. Between 2002 and 2012, the Institut de veille sanitaire recorded nine cases in France (eight of which were imported) among non-vaccinated or inadequately vaccinated subjects. In 2015, a 6-year-old non-vaccinated child died from the disease in Spain. Routine vaccination keeps the disease at bay, individually and collectively.
Why is annual vaccination for influenza necessary?
The influenza virus has dozens of sub-types, and the strains vary from one year to the next. The circulation of these strains (particularly those infectious to humans) is monitored by the WHO which decides on the three or four main strains to be incorporated into the annual vaccine a few months before the influenza season. The vaccine therefore differs from one year to the next. The last-minute emergence of an unexpected strain not having been included in the vaccine can reduce its efficacy.
Identifying misgivings concerning vaccination
In 2010, 61% of the French population had a positive opinion regarding vaccines, versus 90% five years previously. The reason: various controversies surrounding certain vaccines. Nevertheless, confidence is being restored with 79% positive opinions in 2014 according to comparable surveys conducted by the Institut national de prévention et d’éducation pour la santé (Inpes). However, some individuals remain defiant, and continue to question the efficacy and safety of these products. Studies have demonstrated two profiles with greater misgivings:
- individuals with low income and low levels of education, who are inadequately informed about the benefits of vaccination, particularly elderly males and migrants,
- and, in contrast, a highly informed, well-off and educated population, who demand freedom to choose, by evaluating the benefit/risk ratio of the vaccine and sometimes relying on others for protection.
These studies are important so as to more effectively target information on the individual and collective benefit of vaccination, distributed to the different population sub-groups.
Challenges facing research
Vaccine research has a promising future ahead of it. Firstly, because numerous contagious diseases, such as AIDS, hepatitis C, chikungunya virus, SARS, MERS, Ebola, etc. are continuing to spread as no vaccines are currently available. Secondly, because many types of cancer are associated with infection: papillomavirus (HPV) for cancer of the uterus, hepatitis C virus for liver cancer, Epstein-Barr virus for certain types of lymphoma, and Helicobacter pylori for stomach cancer, etc. Developing vaccines against all of these viruses, as is the case for HPV, would thus reduce the incidence of certain types of cancer. And lastly, because therapeutic vaccines are only in the early stages and promise to shake up the 21st century. Great results have already been obtained in the field of cancer, and studies are under way in other areas (Alzheimer's disease, autoimmune disease, AIDS).
Furthermore, there is still room to improve the comfort, tolerability and efficacy of existing vaccines. Hence, a new vaccine for shingles offers 97.2% protection for over 50s, whereas the current vaccine only achieved barely 50% efficacy, falling to 37% after the age of 70.
New design strategies
Several avenues are being explored to make vaccines more effective or to develop new vaccines, particularly against infectious agents for which the inactivation mechanisms are currently unknown:
- neutralization by genetic engineering: This involves rendering an infectious strain harmless by inactivating the genes which make it pathogenic.
- recombinant vaccines and "presenting" microorganisms: This technique involves having a single unique microorganism, usually an innocuous virus which would act as a vector, which expresses the antigens of different pathogenic agents.
- genetic vaccination: This variant of gene therapy involves inserting a fragment of DNA or RNA coding for a vaccine antigen directly into the cells of the person to be vaccinated.
- chimeric vaccines: This technique involves inserting genes of the virus against which an immune response is desired, into the genome of an effective vaccinal strain, already in routine use. This is the case for the dengue vaccines, which will be marketed by 2016. It is made up of the yellow fever virus core and an envelope comprising proteins derived from the four dengue viruses. This approach is also used to develop vaccines for Western Nile virus and Japanese encephalitis. A chimeric vaccine for the Ebola virus, created from the measles vaccine, is also in development at Institut Pasteur.
Several avenues for improvement
Improving the comfort and safety of vaccines is a constant concern. For this purpose, laboratories are working on alternatives to injections, such as the use of skin patches, along with routes of administration via the mucous membranes (oral, nasal, sublingual, rectal or vaginal). Certain vaccines are, moreover, already administered via the oral route (rotavirus) or intranasal route (live attenuated influenza vaccine).
Researchers are also developing new adjuvants and other strategies able to reduce the risk of the absence of response to the vaccine. An Inserm team recently demonstrated that administration of a therapeutic vaccine via the cutaneous route, after performing laser microperforations on the skin, was sufficiently immunogenic, even without an adjuvant. This strategy is based on the fact that the dermis comprises a very large number of antigen-presenting cells which trigger the immune response.
HIV: the challenge ahead
Unfortunately, it is not enough to decide to develop a vaccine in order to achieve this goal, and researchers sometimes come up against major difficulties. This is, for instance, the case for the development of a vaccine against HIV. This virus rapidly mutates, which makes it very difficult to identify antigens common to the different types and sub-types of the virus. Furthermore, it lodges itself in the cells which are supposed to destroy it. Dozens of clinical trials have taken place to date, with no conclusive results. The current strategy involves combining several candidate vaccines so as to optimize the immune response. A vaccine trial was initiated in France in 2014, by the Institut de recherche vaccinale and the Agence nationale de recherches sur le sida et les hépatites (ANRS). It is expected to continue until March 2016.
First vaccines against malaria and dengue, and others under way
The first vaccine against malaria is expected to be marketed shortly. It has received a favorable opinion from the European Medicines Agency. It only offers protection against 30% of serious forms of the disease, but this is the best result obtained to date. Development of a vaccine against malaria has proved difficult owing to the complex nature of the infectious agent responsible for the disease, Plasmodium falciparum. This is a parasite and not a virus or bacteria. Its genome codes for more than 5,000 proteins, expression of which varies considerably depending on the stage of the parasite's life cycle. It can be said that extracting antigens able to protect against all forms of this infectious agent is somewhat complicated.
A vaccine for dengue is also expected to be marketed by 2016. It protects against the disease with 60% efficacy on average. Although efficacy varies according to the viral serotype, the vaccine reduces the number of serious cases by 95% and the number of hospital admissions by 80%.
Furthermore, a vaccine for Clostridium difficile is in phase III of development. C. difficile toxins cause potentially fatal gastrointestinal disorders in approximately 8% to 15% of infected individuals, particularly in the elderly or hospital inpatients (nosocomial infections). Different vaccines for the Ebola virus are also in development. Others are also being studied, such as a vaccine for the chikungunya virus.