Few measures in the field of public health can be compared to the impact of vaccines: they not only provide personal protection to vaccinated people, but they can also provide protection to the community by reducing the spread of infectious diseases within a population.
The control of these diseases is through two modes: prevention, which consists in the optimization of health conditions and vaccination practice, and containment through therapy (not always available) and isolation. The lockdown experienced in Italy from the beginning of March has certainly allowed the containment of the spread of the virus but only the formulation of a vaccine and an adequate global vaccination campaign will allow the complete eradication of the virus, as in the famous case of smallpox, declared definitively eradicated by the WHO in 1980. Indirectly, people who cannot be vaccinated, for example, due to contraindications or are younger than the age for which vaccines are recommended, as well as people who fail to provide an adequate immune response to the vaccine, may be protected from the rest of the vaccinated population. This is due to the fact that by increasing the number of vaccinated people, the circulation of the virus is consequently reduced: therefore, the achievement of high levels of coverage is important not only for personal protection, but also to prevent diseases in vulnerable populations that cannot be protected directly from vaccination.
Vaccines, therefore, represent the only effective weapon against infectious diseases, which have always had a great impact in the history of humanity and their discovery has allowed the extension of human life expectancy by 55 years from 1700 to today, Even more shocking given that 99.99% of the history of humanity’s average life expectancy has been less than 30 years.
The main causes of death until 1900 were in fact infectious diseases, while in the 21st century the main causes of mortality in the world population are chronic diseases where the highest percentage is represented by cancers.
Because viruses are constrained intracellular pathogens, they cannot replicate without the mechanism and metabolism of a host cell.
Today, vaccines being developed and tested have, among many, the goal of the recognition of a protein exposed on the surface of the new coronavirus: glycoprotein spike. It would seem, in fact, that glycoprotein spike is implicated in the process of immune recognition: just the spike protein, which forms "crowns" on the surface of the virus, gives the name coronavirus to the family of viruses which also belongs to SARS-Cov-2.
The researchers' effort consists, consequently, in finding a way to safely introduce this protein into the human organism so that it can elicit an adequate immune response. People often say that vaccines save lives, but that is not entirely true; it is vaccination that saves lives. A vaccine that remains in the vial is 0% effective even if it is the best vaccine in the world.
When will the SARS-Cov-2 vaccine be available?
Recently researchers have been able to make a probabilistic projection on the possibility that a vaccine is authorized for trade over the next few months and years, as shown in the figure below.
Looking at the graphic, by 2020 the probability is really low, while from the beginning of 2021 the probability of approval of a vaccine increases to 14%. The model provides for the possibility of approval of the vaccine to 50% by the end of April or early May 2021, and finally to 85% by the end of 2021 and 98% by the end of 2022. The graphic suggests that it is very likely that the first vaccine will be approved between January and September 2021.
The studies are, of course, based on more or less probabilistic estimates: in the pessimistic scenario, the chances of approving a vaccine in the next three years are just over 80%. Based on these pessimistic assumptions, the average time for approval is April 2022.
In a positive perspective, however, 2021 is the year in which a vaccine becomes more likely to be approved; in 90% of estimates, a vaccine had been approved by the end of March 2021, and in 99% one had been approved by the end of October 2021.
It should, however, be stressed that some events that have not been considered could shift the chances of success for all vaccines: this could include, for example, a mutation in the virus, or a breakthrough in treatment that could reduce the demand for a new vaccine.
To meet the global demand for vaccines, how many doses should be produced?
The probabilistic models analyzed project the time necessary to produce a vaccine in sufficient quantities to ensure the administration to the three risk categories identified by the World Health Organization: health system operators, adults over 65 and young adults with co-morbidity.
To cover the entire population, 18 million doses would be needed. However, according to the studies analyzed, it will be necessary to wait at least December 2021 before the world produces 115 million doses of vaccine, that is the number of doses needed to vaccinate only health professionals in the world.
Will the vaccine be effective?
Regarding the immunity given by a potential vaccine there is still much scepticism: there is some consensus that a two-dose vaccine could give several years of immunity (two to five years was the most commonly mentioned duration). Experts based on the short duration of immunity from natural infection observed in other coronaviruses, such as SARS and MERS: the frequency with which they should be administered is uncertain and likely to vary depending on the vaccine.
What exactly is a vaccine?
By definition, a vaccine is a biological preparation consisting of microorganisms or parts of them which, however, through chemical-physical treatments or genetic manipulation, is made harmless but capable of triggering an effective immune response.
It must have three specific characteristics: safety, effectiveness and practicality.
Since the recipients of the vaccine are basically healthy people, this must be harmless and therefore free of important side effects, it must evoke long-term protection through an appropriate immune response.
Finally, it must be established, easy to administer and cheap, to be accessible to the whole population.
The first scientific realization of a vaccine is to be attributed to Louis Pasteur: he used a culture of chicken broth to develop the vaccine against the "chicken cholera" of 1879/1880. In his laboratory, he sensed that the solution should be preventive (and not therapeutic). Therefore, he constructed a scientific method in which to affirm that the solution resulted in administering to the healthy patient the same agent (antigen) that caused the disease. Five years later, he used the same scientific method to develop the rabies vaccine.
Subsequently, thanks to studies by American scientists Daniel Elmer Salmon and Theobald Smith, it was possible to develop sub-united vaccines composed of inactivated antigens (e.g. proteins, polysaccharides) within live pathogens.
In 1986, a century after the discovery of Pasteur, the first genetically modified vaccine was developed: the recombinant surface antigen vaccine for hepatitis B therapy.
However, until the last two decades, vaccines were used before fully understanding the mechanism of action.
Currently, however, thanks to the increasing availability of sequencing and bioinformatics tools, for the development of this particular drug are provided the so-called "rational" approaches to the design of vaccines.
REQUIREMENTS FOR VACCINE FORMULATION
Today we are aware that live vaccines, and/or to some extent, inactivated, have worked well because they provide the two signals needed to induce immunity: antigen and its natural "adjuvant".
Antigens give the specificity of our acquired immune response to a particular pathogen, while adjuvants, stimulate the innate immune system that has pattern recognition receptors (PRR)which are only capable of recognizing antigens that present molecular models associated with pathogens (PAMPS). Medzhitov and Janeway, 1997
In fact, in order for an antigen to be immunogenic, that is to be able to stimulate the immune system, it must be equipped with a series of molecular structures (PAMP) to trigger those particular receptors (PRR) placed on the cells (in particular dendritic ones) presenting the antigen, these cells called APC, these cells that present antigen via PPR receptors are able, in turn, to stimulate the activation of virgin CD-4+ lymphocytes (called T-helpers), that T-cell series implicated in both innate and acquired immune system response, being able on the one hand to receive the signal generated by APC cells of innate immunity and on the other to activate the proliferation of antibodies by lymphocytes B. Finally, The antigen-antibody attack in turn triggers a cascade of processes leading to viral destruction and/or inactivation.
By observing this activation circuit as a whole, it is therefore possible to understand the relevance of the use of the various adjuvants useful to stimulate model recognition receptors (PRR) expressed on dendritic cells (APC) which, once activated, induce the migration of dendritic cells to draining lymph nodes, where the lymphocytes of the acquired immune system are instructed to assume the functions of "cell suitable" for fighting a certain class of pathogens, using, therefore, the antibody response.
In summary, it can be said that the adjuvant is the non-antigenic component of the vaccine that stimulates the innate immune system, while the antigen is that component of the vaccine that directs the response of the acquired immune system.
Currently, there are several authorized adjuvants that are available for the formulation of vaccines.
Resistance to antibody response
However, it should be remembered that not all viruses can be eradicated by the process described above.
Some viruses have developed some sort of antibody resistance, including:
• HIV-1 (via rapid mutation),
• influenza virus and SARS-Cov-2 (through antigenic drift to avoid detection of previous season antibodies),
• Herpes simplex virus (through the expression of evasin molecules on the surface of the virus making it immune to antibody attack).
For these types of antibody-evasive viruses, we need a different approach to vaccination.
Fortunately, the virus retains some epitopes (molecular models, portions of the virus) that can be used to develop a vaccine that generates immunity directly at the lymphocyte level (in innate immunity), particularly at the level of memory T cells.
Leaving aside the purely technical aspect, in order to develop a vaccine that generates immunity in memory T cells, it should be considered that the vaccine should ensure adequate proliferation of T cells, trained and ready to fight the virus, at the entry site, or at the surface of the mucous membranes.
In fact, unlike the skin, the epithelial layers of our mucous membranes are vulnerable to the entry of pathogens due to the lack of corneification (the stratum corneum is the outermost layer of the skin that acts as a barrier). Considering that most pathogens enter the human body through the mucous membranes, including SARS-Cov-2, it would be appropriate to develop a vaccine that has a particular tropism for our mucous membranes.
TYPES OF VACCINES
Phase II o I/II clinical trials:
- Inactivated SARS-CoV-2 Vaccine (inactivated virus, Chinese Academy of Medical Sciences)
- BBV152 - COVAXIN (inactivated virus, Bharat Biotech International Ltd)
- Recombinant new coronavirus vaccine (CHO cell) (recombined proteins, Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.)
- KBP-201 (recombined proteins, Kentucky BioProcessing Inc.)
- LV-SMENP-DC (recombined cells, Shenzhen Geno-Immune Medical Institute)
- Covid-19/aAPC (recombined cells, Shenzhen Geno-Immune Medical Institute)
- INO-4800 (DNA, Inovio Pharmaceuticals)
- GX-19 (DNA, Genexine Inc.)
- AG0301-COVID19 (DNA, AnGes, Inc., Japan Agency for Medical Research and Development)
- nCov Vaccine (DNA, Cadila Healthcare Ltd)
- COVAC1 (LNP-nCoVsaRNA) (mRNA, Imperial College London)
- CVnCoV Vaccine (mRNA, Curevac)
- EpiVacCorona (recombined proteins, Federal Budgetary Research Institution State Research Center of Virology and Biotechnology "Vector")
- Sanofi-GSK (recombined proteins, Sanofi Pasteur & Glaxo Smith Kline)
Phase III (efficiency e safety):
- Inactivated SARS-CoV-2 (inactivated virus, Sinovac e Butantan Institute)
- Inactivated Novel Coronavirus Pneumonia (COVID-19) vaccine (inactivated virus, Hennan Provincial Center for Disease Control and Prevention e Sinopharm)
- BBIBP-CorV (inactivated virus, Beijing Institute of Biological Products Co., LTD e Laboratory Elea Phoenix S.A.)
- AZD1222 (vaccine carrier, University of Oxford e Astra Zeneca)
- mRNA-1273 (mRNA, National Institute of Allergy and Infectious Diseases e Moderna)
- BNT162 (mRNA, BioNTech RNA Pharmaceuticals e Pfizer)
- Ad26.COV2.S (vaccine carrier, Janssen Vaccines & Prevention (Johnson & Johnson))
- Ad5-nCoV (vaccine carrier, CanSino Biologics)
- Gam-COVID-Vac (vaccine carrier, Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation)
- Inactivated Novel Coronavirus Pneumonia (COVID-19) vaccine (Vero cells) (virus inattivato, Wuhan Provincial Center for Disease Control and Prevention)
- NVX-CoV2373 (recombined proteins, Novavax)
The main types of vaccine in clinical phase that could be available from the first months of 2021 are:
● mRNA-1273 (MODERNA)
Messenger RNA vaccine (mRNA) whose main developer is the Moderna company.
The sequencing (in other words “reading") of the viral genome has made it possible to identify the protein regions of the virus that can be used to trigger the antigenic response. In this case the mRNA expresses the trimer of the Spike protein present on the viral surface that allows interaction with human cells at the level of the ACE2 receptor.
The vaccine is able to trigger a powerful antibody response to the virus circulating in the human population by activating CD8+ cells which trigger the alarm and thus protect our body from infections borne by the respiratory system. The aim is, therefore, to increase the production of antibodies capable of neutralizing the Spike proteins of the virus by preventing the entry of the viral genome into the host cell.
Phase I studies have demonstrated the safety of the vaccine. Anthony Fauci, immunologist and director of the National Institute of Infectious Diseases in the United States stated, during an interview with NBC :"The data of Moderna on the vaccine against Covid-19 are extraordinary, 94.5% effectiveness is impressive.... It’s a big step forward. We expect doses at the end of December for high-risk categories".
Made by CanSino Biologicals using a virus (adenovirus type 5 with reduced replicative capacity) that acts as a vector for the expression of the protein Spike coronavirus. Adenovirus serves as an envelope to present the spike protein to the immune system, so that it is able to produce antibodies in case it undergoes the actual viral infection.
It has been shown that the inoculum of a single dose of that vaccine allows protection from respiratory tract infection in mice. Intramuscular administration resulted in a strong immune response, both humoral and cell-mediated.
According to the latest updates regarding 7 September 2020, the vaccine is in phase 3 in Russia.
● INO -4800
It is a INOVIO Pharmaceutical DNA vaccine and consists of a circular DNA fragment called "pGx9501 plasmid", coding for the entire Sars-Cov-2 Spike glycoprotein range.
Studies were carried out on the level of immunization of mice and the specific antigen response of T cells was measured, the presence of antibodies to counteract the infection and, finally, the biodistribution of antibodies at the lung level. These studies identified INO as a valid candidate for vaccine formulation.
It has now been tested on non-human primates which were given two doses four weeks later, 13 weeks after the last inoculum were re-injected and the results were encouraging: reduced viral load and presence of cell-mediated immune response which is the indispensable one for the formation of antibodies. In addition, it is stable at room temperatures for more than a year and does not require freezing to be carried, feature of certain benefit to the mass immunization campaign.
Dr. J. Joseph Kim, president and CEO of the company, stated: "INOVIO continues to focus on developing our vaccine COVID-19, INO-4800, as well as advancing our other basic DNA medicine programs.... While the partial clinical wait for INO-4800 has led to delays to our originally planned development timeline, the company remains well capitalized and focused as both clinical trials and production efforts continue"
The late tests of the candidate for the Inovio coronavirus vaccine -- INO-4800 -- have been under a "partial clinical suspension" by the Food and Drug Administration since late September, by this month (November 2020) instead the FDA (Food and Drug Administration) should decide whether or not to give the okay to resume studies at an advanced stage (Phase II/III).
● LV SMENP DC
Vaccine developed by Shenzhen Gene-Immune medical instituted, based on the engineering of a synthetic minigene consisting of preserved domains of the structural proteins of the virus and a polyprotein protease. In this case the vaccine is carried by a lentivirus, a type of retrovirus with genome consisting of RNA molecules that has had a considerable development in the field of gene therapy.
In this case the genes are linked to the expression of viral proteins that mediate the entry of the virus into cells but also immunomodulatory genes that stimulate the activation of T cells. The vaccine is administered by subcutaneous injection, following the patients included in the study for one month after infusion, monthly for the first 3 months and finally every 3 months until the end of the study.
On 24 March 2020, the multicenter phase I study of this vaccine began, which will continue through a series of checks and follow-up until 31 December 2024.
As of August 2020, this vaccine is being tested for prophylaxis against COVID-19 in human clinical trials.
Among the numerous developmental research in this sense stands out the one related to the BCG vaccine: this drug can improve the innate immune response, stimulating, in addition to memory T cells, also natural killer cells (NK), monocytes and macrophages and, consequently, it can provide protection against other pathogens not closely related to mycobacteria tuberculosis.2,3
Since the vaccine is inactivated but alive, there is a probability that in individuals with HIV or immunocompromised, this does not work.
A recent study has shown that BCG vaccination can induce a specific immunity against SARS-Cov-2 because it allows the recognition of the viral envelope protein to our immune system, which is essential for infectivity.4
In addition, other studies have found fewer infections and deaths from SARS-Cov-2 in regions vaccinated with BCG and, in this context, lower hospitalisation rates have been found in the North East US communities, even decades after vaccination.5–7
The same evidence is also confirmed in Japan where Kinoshita et al.13 found that the prevalence of SARS-Cov-2 infection was inversely associated with BCG vaccination coverage.
By analysing the safety profile of this vaccine through the results of the Phase III ACTIVATE study, it can be seen that the BCG vaccination was safe and could protect the elderly from infection, particularly respiratory infections of likely viral origin. In addition, no difference in the frequency of adverse effects between the BCG and placebo groups was found.
Administration of vaccines
The administration of vaccines is a well-established practice, regulated by national procedures and guidelines.
The administration of vaccines is a procedure of medical and nursing competence, which is carried out in suitable rooms where it is possible to ensure the maximum safety of the patient who undergoes vaccination and to manage any small complications.
The checks to be carried out before vaccination:
• Nursing control phase of equipment/surgery::
every morning control of refrigerators temperature , to verify that the vaccines have been stored properly. In particular, the Pharmacopoeia suggests that a minimum temperature of 2° C and a maximum of 8° C should be maintained;
it shall be verified that the first-aid equipment is in order and functioning (defibrillator, emergency plates and trolley);
medicines, their expiration dates, the number of batches are checked, and whether the package is intact and undamaged or partially opened.
These controls are essential to prevent adverse reactions dictated by the bad storage of the drug and to be able to act quickly in case the subject develops complications.
• Identification phase and remote medical history:
name, last name and date of birth to avoid misadministration (if the person is a minor, he or she must be accompanied by a parent);
asses the current state of health;
assess whether it has already carried out other vaccination doses and whether it has had complications;
if you haveallergies to the medications;
if the person concerned has a medical condition;
educate the patient who will carry out the vaccine about the procedure to be carried out, any complications and responds to any doubts.
If the nurse has any doubts about the state of health of the patient or about any contraindications to the vaccine will call the doctor for further information.
● Preparation phase for vaccination:
▪ check that the medication is the one prescribed by your doctor;
● Preparation phase of the drug:
▪ dilute the drug with the diluent provided by the company and verify that the lyophilized is all soluble;
▪ wash hands;
● Stage of preparation for administration (which will be chosen on a case-by-case basis according to the patient’s physique and the site of administration):
▪ wear disposable gloves ;
▪ disinfect the skin with 2% chlorhexidine, or with alcohol-based disinfectant with circular movements, leave to act in the indicated time;;
The preparation of the material, the operator and the skin is a fundamental phase as it will allow us to perform the maneuver in an ideal hygienic condition and in safety for the assisted and for the nurse.
Method of administration and sites:
Usually vaccines are administered subcutaneously or intramuscularly, in the case of flu vaccines can also use an intradermal injection.
For the choice of the route of administration follow the manufacturer’s instructions.
Let’s proceed more specifically:
➢ INTRAMUSCOLAR injection:
▪ in children under 12 months old the preferred area is the anterolateral area of the thigh;
▪ in children over 12 months old and up to 2 years old, the deltoid area may be used if the musculature is sufficiently developed otherwise the anterolateral area of the thigh is preferred;
▪ the deltoid muscle is preferred from the age of 3 to 19, but the anterolateral part of the thigh may also be used;
▪ for adults, the chosen place of insertion is the deltoid area.
After disinfecting the selected area, you insert the needle with an angle of 90 º, directly into the muscle after performing the Z-track method.
Once the drug is injected, the needle is always extracted at 90 º swiftly, you place above the insertion point a disinfectant swab massaging the area to facilitate the spread (absorption) of the drug. Then, you proceed to dispose of the needle in the appropriate container for cutting edges (do not chase the needle because you risk to injure), dispose of gloves and wash your hands.
➢ SUBCUTANEOUS injection :
▪ in children under 12 months old will be administered in the thigh;
▪ in children over 12 months old and in the adult the upper outer area of the triceps is used;
Also in this case the operator will have to prepare all the material to work safely using disposable devices. Wash hands, wear disposable gloves, and disinfect the patient’s skin.
The injection should be carried out at an angle of 45 º with the dominant hand. The non-dominant hand will create a skin fold to highlight the subcutaneous tissue. The skin fold will be maintained for the duration of the injection and released at the time of removal of the needle. Also in this case it’s advisable to apply a disinfectant swab over the insertion site, performing a slight pressure, but in this case you will not have to massage the area. Last but not least, the proper disposal of the needles must take place immediately.
➢ INTRADERMAL injection:
it’s carried out on the volar surface of the forearm, with an angle parallel to the long axis, and therefore an angle of about 15°. In this case it is necessary to disinfect the skin, then stretch the skin, prick and observe the appearance of a small weal. At the end of the injection, place a disinfectant swab gently without pressing to prevent the spreading of the drug to the underlying tissues. The materials used are then disposed of as in previous vaccination procedures.
After the vaccination session:
✔ ensure that all the material has been disposed of correctly;
✔ record the date, the type of vaccine administered on the vaccination booklet;
✔ monitor the patient for 15/30 minutes to avoid the risk of complications.
What are the main complications?
The most frequent complication is undoubtedly fever, but in some cases it can be accompanied by convulsions. More rarely, however, severe allergic reactions such as anaphylactic shock can occur.
Usually these manifestations occur immediately or within a few minutes of administration, for this reason it is important to keep the patient in monitoring for a few minutes at the end of the session.
These severe allergic reactions are managed by the doctor and the health care provider in an environment as suitable as that of an outpatient care unit. The clinic is equipped with all the necessary equipment to manage these complications and it is the responsibility of the nurse to check daily the correct supply and operation.
It should also be remembered that most complications (except for anaphylactic shock) resolve spontaneously without the need to intervene pharmacologically.
In addition, complications include:
• the temporary reduction of platelets (platelets openia, 1 case per 30,000) following vaccination measles, mumps and rubella;
• lipothymia: with immediate onset, characterized by loss of consciousness, pale and sweaty skin, bradycardia (slowing of heart beats), hypotension (lowering of blood pressure) and nausea. It resolves without the use of drugs and is a complication of non-allergic type;
• hypotonic-hyporesponsive episode: it also occurs within a few minutes and it’s characterized by decreased vigilance accompanied by pallor or cyanosis and muscular hypotonia, also in this case we speak of non-allergic reaction;
• convulsive crisis: usually it develops in subjects who already suffer from it or from the psychological stress caused by the injection. In this case, the doctor and the nurse will implement the emergency protocols provided by the hospital of reference;
• anaphylactic shock: it’s a very rare complication, about 1 case per million vaccinated. It is a severe systemic and generalized allergic reaction, presenting the following symptoms: itching, burning, lacrimation, angioedema, dizziness, nausea, chest tightness, hives, wheezing (difficulty breathing), abdominal pain, arrhythmia, collapse. In this case too, health professionals will apply the company emergency protocols provided for. In particular, the primary aim will be to ensure the support of vital functions and to allow the timely intervention of 118.
Curiosities and useful questions:
1. Should we fast before getting a vaccine?
No, there’s no fasting before the vaccine.
2. Can we get it if we have fever?
It would be appropriate to get it in a good state of health.
3. Can the vaccine cause autism?
NO! We’ve already talked about it in this article.
4. Can you get the injection in an area of the body where there are tattoos?
Yes, there are no contraindications.
5. I’m pregnant, can I get vaccinated?
Live attenuated virus vaccines (such as measles, rubella, mumps and chickenpox) are contraindicated as a general precaution. As a general rule, after vaccination the woman should try to wait at least a month before conceiving. However, there are no studies that show an increase in the risk of foetal malformations caused by vaccines taken incorrectly during pregnancy. Inactivated vaccines (delayed, tetanus, whooping cough) can be safely administered during pregnancy. The flu vaccine is recommended for women, who at the beginning of the epidemic season are in the second and third trimester of pregnancy.
6. Is it harmful to administer more than one vaccine at the same time?
There are no studies that demonstrate this thesis; in fact, in the case of administration to a child you reduce the stress of multiple injections and have to go several times to the vaccination center, with the consequent risk of skipping some administration.
7. Do the vaccines given to infants lead to a greater risk of becoming allergic to them as adults?
There is no correlation between the two, on the contrary studies show a protective effect induced by the vaccine.
Vaccine and Vaccine-Vigilance
After placing on the market and administration in a wider and more clinically diverse population, the vaccines are subject to post marketing monitoring, in this case vaccine-vigilance, to identify and classify any unexpected post-immunization adverse reactions (Adverse Effects Following Immunization, AEFI), which have not been detected in pre-authorization clinical and epidemiological studies.
Unlike drugs, in the surveillance of vaccines (vaccine-vigilance), an obstacle concerns the peculiar frequency of administration (usually they are administered only once, at most 3, in the lifetime of an individual) therefore it is rather difficult to collect sufficient data in the “dechallenge”(observation of effects following suspension) of the “rechallenge” (resumption of administration).
Therefore, vaccine-vigilance studies are mostly oriented to the safety of use in relation to:
● the intrinsic properties of the vaccine
● the quality of the product
● the suitability of the prescription to a particular patient or group of patients
● the correct method of preparation and administration
AEFI and causality assessment: what effects does the vaccine have?
An adverse reaction after immunization is not always related to the vaccine administered, but also to coincident events, such as:
1. pre-existing or newly acquired disease (due to genetic predisposition);
2. spontaneous occurrence of an event without known risk factors;
3. previous exposure to drugs or toxins;
4. complications resulting from surgery;
5. the occurrence or aggravation of an infectious complication already present in the organism, but not manifested during the vaccination event.
Therefore, adverse effects of post-immunization consistently related to vaccination are due to vaccine quality defects, immunization errors and immunization anxiety.
In the first case, local effects such as pain at injection, redness, localized or diffuse edema (especially in the limbs) and systemic effects such as fever or lethargy, and in severe cases thrombocytopenia, hives and demyelination may occur.
The errors in the immunization derive, instead, from:
● inappropriate handling (for preparation and storage): these errors cause inactivation of the vaccine, which therefore does not perform its protective serum function, or loss of power of the vaccine, so the expected immune response does not take place, or is insufficient,
● a non-adherent prescription (hypersensitive or immunocompromised subject). A person not suitable for the prescription may develop anaphylaxis, disseminated infections or the development of the disease for which vaccination coverage was planned
● incorrect administration of the vaccine (wrong dose, ineffective route of administration, length of needle unfit): local or systemic reactions may take place seen for errors related to the vaccine product or quality, and in particular neurological lesions, muscular, vascular or bony.
These issues are preventable through training and capacity building of the operators involved and are examined first in the post reporting survey. .
They are due, instead, to anxiety:
o vasovagal mediated reactions (e.g.: fainting);
o hyperventilation mediated reactions (wheezing and tachycardia);
o psychogenic disorders related to stress.
To overcome this type of reactions, as described above, vaccination must be carried out in a safe space, even more so in this emergency by covid-19.
(EMP), D. d. (2013). Causality assessment of an adverse effect Following Immunization. User manual for the revised WHO classification. World Health Organization.
Reporting of AEFI to competent authorities in Italy
The National Pharmacovigilance Network, established by the Italian Drug Agency (AIFA) in 2001, collects spontaneous reports made by doctors, healthcare professionals and patients within the Vigifarmaco platform. These reports can be made by filling in the electronic form directly on the platform, or by sending the paper form prepared by the AIFA by post, fax or e-mail to the Head of Pharmacovigilance of the structure of territorial competence. The latter will then send the information to the Qualified Person for Pharmacovigilance of the Manufacturer.
On the basis of the analysis of the reports submitted, pharmacovigilance experts from all the parties involved conduct targeted pharmaco-epidemiological studies.
As regards the monitoring of vaccines, the AIFA established in 2010 the Supervisory Vaccine Working Group, which, in addition to the studies mentioned above aimed at assessing the risk/benefit ratio, deepens relevant topics in the regulatory and scientific field and promotes communication between citizens and health professionals, disseminating essential information in a language comprehensible to all audiences. To this end, the Group periodically draws up two documents: the Report on post-marketing surveillance of vaccines in Italy and the Guidelines for the evaluation of adverse reactions. The first is an account of the analysis of the reports received, the studies carried out accordingly, their results and conclusions on the subject. The second is a handbook that contains the definitions and procedures explained in the previous paragraphs of this section of the article.
The members are representatives of the Ministry of Health, the Higher Institute of Health and the Regional Pharmacovigilance and Prevention Centers, which also make use of ad hoc experts.
AIFA. (2017). The vaccine-vigilance in Italy: role and objectives. Rome: Working group on vaccine-vigilance.
The assessment of causality in post-immunization adverse events consists in assessing the three types of errors described above and it’s oriented towards safe and low-risk immunization. In particular, it aims to exclude in the first place any immunization errors, to help improve the effectiveness of the vaccine.
A later detection of non-compliances in the product or in the quality is, instead, functional to the assessment of the risk/benefit ratio, because in an optimal preparation, this relationship must lean in favor of the term denominator.
The projects and related activities are based on a coordinated work of Pharmacovigilance Managers of health structures and Regions of Competence, Manufacturers and National and International Drug Agencies, each with its own defined role.
It is of fundamental importance to communicate with the citizens and the local health workers, who are the main actors in a long and articulated process, which is all in the community’s favor.
 Jeyanathan, M., Afkhami, S., Smaill, F. et al. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol 20, 615–632 (2020). https://doi.org/10.1038/s41577-020-00434-6