Flu vaccination | Pediatría integral

Virology Unit. Microbiology Department. Son Espases University Hospital. School of Medicine, University of the Balearic Islands. Palma de Mallorca

Corresponding author:

jorge.reina@ssib.es

Human influenza is an acute disease caused mainly by influenza A and B viruses that occurs annually as seasonal epidemic outbreaks in the winter, with an average duration of 8-12 weeks, or sporadically as a pandemic. Various epidemiological studies have shown that preschool and school-aged children have the highest rates of influenza infection in all countries and epidemic seasons, ranging from 15% to 42% of this population. Current vaccination rates for children against influenza are very low, despite the risk of hospitalization due to infectious complications in children under 5 years of age. From a practical standpoint, only two types of vaccines should be considered: those consisting of viral antigenic fragments (inactivated) and those consisting of attenuated viral suspensions (attenuated). Since 2012, all influenza vaccines were required by WHO to contain two strains of influenza A virus (subtypes H3N2 and H1N1) and two strains of influenza B virus (Victoria and Yamagata lineages), although since 2023 the WHO has returned to recommending only trivalent vaccines without the presence of the Yamagata lineage due to its possible extinction.

La gripe humana es una enfermedad aguda causada preferentemente por los virus gripales A y B, que se presenta anualmente como brotes epidémicos estacionales en la época invernal, con una duración media de 8-12 semanas, o bien de forma esporádica o como pandemia. Los diferentes estudios epidemiológicos han demostrado que la población infantil preescolar y escolar es la que presenta las mayores tasas de ataque gripales en todos los países y temporadas epidémicas, oscilando entre el 15-42 % de esta población. Los porcentajes actuales de población infantil vacunada contra la gripe son muy bajos, a pesar del riesgo de hospitalización por complicaciones infecciosas en los niños menores de 5 años. Desde el punto de vista práctico, solo deberían considerarse dos tipos de vacunas: las constituidas por fragmentos antigénicos virales (inactivadas) y las formadas por suspensiones víricas atenuadas (atenuadas). Desde 2012, todas las vacunas de la gripe debían contener, por recomendación de la OMS, dos cepas del virus gripal A (subtipos H3N2 y H1N1) y dos cepas del virus gripal B (linajes Victoria y Yamagata), aunque, desde 2023, la OMS ha vuelto a recomendar solo las vacunas trivalentes sin la presencia del linaje Yamagata por su posible extinción.

Key words:Influenza; Influenza viruses; Epidemiology; Vaccines.

Palabras clave:Gripe; Virus gripales; Epidemiología; Vacunas.

• To understand the general characteristics of influenza viruses and their respiratory pathogenesis.

• To learn what the main implications of flu viruses are in the development of the disease.

• To identify the main epidemiological and clinical aspects of influenza in the child population.

• To distinguish between the various types of flu vaccines and their applications.

• To recognize the main indications for flu vaccine according to international and national recommendations.

https://doi.org/10.63149/j.pedint.97

Influenza is one of the main respiratory illnesses affecting children. Influenza viruses have several characteristics that make them unpredictable.

From a taxonomic point of view, human influenza viruses belong to theOrthomyxoviridaefamily and theInfluenzavirusA, B, and C genera. These viruses have a single-stranded RNA genome made up of 8 genetic segments (approximately 12,000-14,000 nucleotides in total) of varying sizes that encode about 10-12 different proteins. Among them, segment 4 encodes hemagglutinin (HA) and segment 6 encodes neuraminidase (NA)(1).

The tissue tropism (respiratory tract) of human influenza viruses is not determined exclusively by the presence of the cell receptor, which seems logical, given that sialic or neuraminic acid is found on the surface of a large number and type of human cells, but by the tissue presence of enzymes (proteases) with the ability to activate the HA glycoprotein, conferring infectivity.

From a genetic standpoint, influenza strains develop a series of point mutations in the HA gene, which are selected by the selective pressure of the human immune system. This process selects variants with genetic and antigenic changes that accumulate, leading to antigenic drift. These variants, if they become dominant over others, are the origin of seasonal influenza epidemics and, in part, responsible for the annual need to update and change the antigenic composition of vaccines each season. In addition, influenza A viruses can undergo a phenomenon called genetic reassortment, whereby genomic segments are exchanged between different animal or human subtypes. When these segments affect hemagglutinin, they can lead to the emergence of a new subtype with pandemic potential(1,2).

From an epidemiological standpoint, influenza A should be considered an anthropozoonosis, meaning it has an animal reservoir, while influenza B is an anthroponosis, with humans as its only reservoir. Influenza C, with little impact on humans, has both humans and pigs as reservoirs. Thus, against influenza A, we can only protect ourselves through vaccination or treatment of infected individuals; that is, it is a non-eradicable infection, since we cannot eliminate the reservoir. In contrast, influenza B could be eliminated from humans through a universal vaccination program with a highly effective vaccine(1,2).

Human influenza is an acute illness caused primarily by influenza A and B viruses. It occurs annually as seasonal outbreaks during the winter months, with an average duration of 8-12 weeks. Influenza A is the only strain capable of causing pandemics with an unknown frequency. Influenza is generally considered a mild and self-limiting illness, with an incubation period of 2-3 days and a symptomatic period of approximately 5-7 days. Symptoms include sudden onset, fever, pharyngitis, malaise, myalgia, and respiratory symptoms. Its main public health impact is its high attack rate (affecting nearly 50% of the exposed population) and morbidity, particularly at the extreme ages of life, although it is generally associated with low mortality (between 0-1% overall and 10% of severe hospitalized cases).

As mentioned, influenza is a zoonotic disease; therefore, the only and best way to prevent it, especially in at-risk groups, is through annual vaccination programs. Despite these recommendations, vaccination rates in Spain for those over 65 do not exceed 45%, while the WHO recommends rates of 75%. With such a low vaccination rate, only individual protection against influenza is achieved, along with a reduction in complications and hospitalizations, but not herd immunity, which would be desirable to interrupt viral circulation.

In general, influenza has only been considered a severe illness in children with underlying chronic diseases, representing approximately 10% of the population, in whom an increased risk of complications can be identified. Despite this, most epidemiological studies demonstrate that children are responsible for the introduction, spread, and, very likely, the maintenance of influenza in the community(3).

The socio-health impact of influenza on the child population, as well as on the general population, varies widely each season and depends, among other factors, on the virulence of the circulating influenza strain, the degree of prior immunity of the population and the ability of the strain to spread among it, although this age group continues to be the most affected, with the accumulation of cases in a short period of time being especially important(4).

Various epidemiological studies have shown that preschool and school-aged children have the highest rates of influenza infection in all countries and epidemic seasons, ranging from 15% to 42% of this population. Studies conducted during different influenza seasons have shown that annual rates of children visiting medical clinics due to influenza infection range from 6% to 29%. Furthermore, influenza infection and its complications lead to a 10% to 30% increase in the number of antibiotic treatments prescribed to children during influenza season. It has also been observed that during the early stages of influenza epidemics, there is a predominance of cases in children, and that school absenteeism is a factor that precedes community spread of influenza. One of the main causes of this phenomenon is the greater susceptibility of the child population to the new antigenic variants of the virus and the fact that infected children excrete the influenza virus in greater quantities (viral load) and for a longer time in respiratory secretions(5).

Although influenza-associated mortality is much lower in children (0.2-0.8/100,000) than in the elderly (over 65 years), influenza infection facilitates bacterial complications in otherwise healthy children and can manifest as other infections beyond the respiratory tract. The most serious complications of influenza infection, such as encephalopathies and sudden death, have not been fully studied, although the first data on these conditions were presented during the 2023-2024 influenza season, with an estimated mortality rate of 3.8/100,000 in children under 2 years of age. One of the main complications of childhood influenza is acute otitis media, which occurs in approximately 20% of confirmed cases; bronchiolitis and sinusitis are also common complications and could benefit from an influenza vaccination program. It should be remembered that 70% of children aged 0-5 years hospitalized for severe influenza and 56% of ICU admissions do not present any risk factors, while 80% of hospitalized patients who died present one or more factors(5).

Current percentages of children vaccinated against the flu are very low, despite the fact that the risk of hospitalization due to infectious complications in children under 5 years of age is at least as high as that observed in people over 65 years of age, differing clearly from them in that less than 30% of this child population has underlying chronic conditions that predispose them to the flu.

The reasons for this low vaccination coverage are not fully understood, but it could be due to multiple factors that contribute to a certain historical and resigned resistance regarding the importance of pediatric influenza. These factors could include the need for annual vaccination within a comprehensive vaccination schedule during the first two years of life. Other contributing factors are: the limited information available on influenza morbidity and mortality in children; the epidemiological difficulty in assessing the true impact of vaccination (vaccine effectiveness); the existence of only a few officially recognized indications, based exclusively on studies conducted on adults; the lower demonstrated efficacy of the influenza vaccine compared to other routine vaccines; the existence of some misconceptions about the true contraindications of vaccines in general; and the existence of fears, generally unfounded, about adverse vaccine reactions(5-7).

From a practical point of view, only two types of vaccines should be considered: those made up of viral antigenic fragments (inactivated vaccines) and those made up of suspensions of attenuated viruses (attenuated or live vaccines), although there are several other types (Table I).

Inactivated vaccines

Inactivated vaccines, which are non-infectious, are the most widely used. They consist exclusively of the influenza hemagglutinin (HA) of each strain.

Of the inactivated vaccines, which lack the capacity for viral infection, there are basically three types: a) whole-virus vaccines, composed of purified suspensions of whole viruses inactivated with chemical compounds; b) split-virus vaccines, composed of purified suspensions of virions that have been split using detergent-type substances and which contain primarily the HA and NA glycoproteins and, partially, the NP nucleoprotein and the M protein; and c) vaccines consisting exclusively of purified HA surface glycoproteins (subunit vaccines). The latter are the most widely used in most vaccination programs. The vaccine contains 15 µg of HA from each of the vaccine strains (45 µg total); in addition, there are high-dose inactivated vaccines that contain 60 µg of each strain and are only recommended for the adult population. Inactivated vaccines can be obtained from embryonated eggs or cell cultures (approved for >6 months) and require a very complex antigen extraction process, so each egg only provides one vaccine dose (Fig. 1). These protein-based inactivated vaccines can be subdivided into adjuvanted and non-adjuvanted vaccines; only the former are indicated for adults. The adjuvant is a complex lipid compound that non-specifically stimulates the immune system and elicits a greater response to the associated antigen(5,8,9).

Figure 1.Process of manufacturing inactivated vaccines consisting exclusively of hemagglutinin as the antigen.

Since 2012, all influenza vaccines were recommended by the WHO to contain two strains of influenza A virus (subtypes H3N2 and H1N1) and two strains of influenza B virus (Victoria and Yamagata lineages). However, since 2023, the WHO has again recommended only trivalent vaccines without the Yamagata lineage, which is officially extinct. Antigenic selection of each strain is performed annually based on surveillance and control studies conducted in global reference laboratories(10).

Most epidemiological studies of post-vaccination follow-up have demonstrated that most healthy individuals respond to the vaccine with a high level of neutralizing antibodies capable of preventing influenza infection. These vaccines only induce a systemic response in IgG antibodies that concentrate in the lung parenchyma; therefore, vaccinated individuals can still become infected with and transmit influenza, but they are protected from the disease and its complications. However, vaccine efficacy will depend primarily on the degree of antigenic homology between the vaccine strain and the epidemic strain, the age of the individual (greater efficacy in young people and adults), and the presence or absence of underlying pathologies, both immunological and of other kinds. In influenza vaccination, the aim is not only to avoid the risk of infection, which would be desirable, but, in general, it is sufficient to prevent or minimize the development of the disease and its serious complications and hospitalization(2,10).

One of the main drawbacks of current inactivated split vaccines is their administration by injection, which requires the use of needles and is a method of administration that is not very acceptable to vaccinated personnel. The most frequent adverse effects of inactivated influenza vaccines are pain at the injection site, fever, muscle aches, and fatigue (5-20%). This vaccine has not been shown to pose a risk for developing Guillain-Barré syndrome; the risk is higher with natural influenza infection.

Attenuated vaccines

Live attenuated vaccines consist of suspensions of live viruses, but with reduced replication. They can be administered nasally.

Live attenuated vaccines are composed of suspensions of live virus and are more difficult to obtain, produce, and standardize(11). The development of influenza strains capable of replicating at non-physiological temperatures (30°C) has allowed to produce live, but attenuated, vaccines designated as “cold-adapted” (ca+). These vaccines also have a reduced capacity to grow at 38-39°C (temperature-sensitive phenotype; ts+) and restricted replication in the respiratory tract (att+). These vaccines are obtained using a previously attenuated donor master strain, which is grown alongside the candidate vaccine strain. As a result of genetic exchange during viral replication, new hybrid strains are formed, consisting of six genes from the donor strain and two from the vaccine strain (6+2 strain), corresponding to the HA and NA genes. One of the advantages of these vaccines is that up to 15 vaccine doses can be obtained from each embryonated egg, since replication and progeny are very high (Fig. 2).

Figure 2.Process of manufacturing attenuated vaccines, made up of each of the recommended strains.

Clinical trials with these vaccines have demonstrated their high immunological efficacy and protective capacity, both against the flu itself and against one of its main complications, febrile otitis media. In general, they are considered to provide an average of 80% protection against confirmed influenza compared to a placebo, which is higher than that of inactivated vaccines. These vaccines, when administered nasally, induce a potent immune response with IgA antibodies and a smaller IgG response, which prevent influenza infection in the oropharynx (“sterilizing”) and its subsequent spread to the lungs. Thus, vaccinated individuals are not contagious and do not transmit the disease, breaking the chain of epidemiological transmission. Furthermore, as an added advantage, these vaccines are administered only once intranasally, eliminating the need for syringes and increasing their acceptability. These vaccines, like inactivated vaccines, are updated annually with the predominant antigenic strains after cold attenuation. Some authors postulate that the use of whole viruses would provide a broader set of antigenic determinants (broad spectrum); so that, in the face of a possible disparity between the vaccine strain and the epidemic strain, antibodies directed against other antigens would provide greater protection against the new strain(11-14).

The “original antigenic sin” is an immunological phenomenon that establishes that the first exposure to the influenza virus in childhood produces an immune imprint that will condition the future response against other antigenically related influenza strains. Due to the predominance of this imprint, subsequent responses can negatively interfere with new vaccine strains. However, vaccination in early childhood with a vaccine made up of whole viruses (intranasal attenuated vaccine) can be beneficial, as it produces a much broader antigenic imprint (four strains) than a natural infection (a single strain); therefore, its application could be considered an “antigenic blessing” that would strengthen the immune response against influenza(15).

Numerous studies have demonstrated the safety of the intranasal flu vaccine, with the few adverse effects described being nasal congestion and fever. However, caution should be exercised in children with severe asthma or active wheezing. Due to its attenuated nature, it should not be administered to immunocompromised children. Although an aerosol may be produced during administration, it cannot infect those nearby, as the vaccine is rapidly absorbed by the nasal mucosa. Vaccinated individuals excrete influenza viruses through their nostrils for 2-3 days, but the attenuated nature of the virus makes transmission difficult, and if it does occur, it does not cause illness in those exposed. Since the introduction of these vaccines, some vaccine viruses have been detected by PCR in the nasal passages of children with other viral respiratory illnesses. These viruses, and especially type B viruses, must be genetically characterized to differentiate them from wild viruses, particularly the Yamagata lineage of influenza B, apparently extinct and recently eliminated from these vaccines(12-14).

There are multiple vaccine platforms that attempt to improve immunogenicity. Messenger RNA (mRNA) vaccines offer additional advantages.

In addition to the vaccines mentioned above, virosomal vaccines should be noted. These are made using phospholipid compounds to form vesicles (virus-like particles or VLPs), on the exterior of which the HA and NA proteins of the influenza virus are arranged. This presentation allows for vaccines that mimic the structure and arrangement of whole viruses without the reactogenic component of the internal proteins but simulating complete virions. This modifies the antigen processing pathway and results in enhanced immunogenicity(16).

Recombinant vaccines are obtained by inserting the influenza HA gene into the genome of an insect virus (baculovirus) and then culturing it in insect cells, followed by the extraction and purification of the vaccine HA. These vaccines are called recombinant protein vaccines and contain a concentration of 45 µg of each HA component. Due to their protein nature, they must be combined with an adjuvant to enhance their immune response; currently, they are only indicated for the adult population(17,18).

The latest vaccines in development are messenger RNA (mRNA) vaccines. These vaccines use mRNA encoding influenza HA encapsulated in a lipid nanoparticle that is injected into the host (Fig. 3).

Figure 3.Schematic of the composition of the conventional messenger RNA vaccine against the influenza virus based on hemagglutinin (HA).

In this case, the human cells themselves translate this mRNA into vaccine protein and secrete it to be recognized by the immune system, both humoral and cellular. mRNA influenza vaccines offer several advantages over other types of vaccines, such as: a) a very favorable safety profile (RNA is a non-infectious molecule, not integrable into the cellular genome, and is rapidly degraded by cytoplasmic RNases); b) a highly controllable production process for the target RNA with high antigenic identity, since it is produced similarly to the viral replication process in natural infection by the human cell itself; c) rapid and scalable production, requiring little time for initial production or subsequent upgrades; and d) it does not require the use of embryonated eggs or cell cultures that may alter the antigenicity of the final protein(19).

One of the disadvantages is that they must contain high doses of nanoparticles with the consequent local effects, but their great advantage is that the antigenic identity of the HA synthesized by the cells is close to 100% of the original protein. In the other vaccines, inactivated and recombinant, the antigenic identity is always lower because they are produced using non-human elements (eggs or animal cells).

Current vaccines need to be updated each season due to the variability of the influenza virus. For this reason, the WHO has been promoting the development of so-called universal vaccines for years. These vaccines would protect against the main influenza viruses, require only one dose, and provide lasting immunity for more than 5 years. Currently, several platforms exist with these objectives, notably an mRNA vaccine against the 20 known influenza subtypes and another based on immunity against the constant part of the HA (the stem), which requires several sequential immunizations to achieve good cross-immunity between them(20,21).

The guidelines and recommendations for the flu vaccine are established by health authorities worldwide. Each country adopts these guidelines through its vaccination committees.

In 2012, the World Health Organization (WHO) recommended that all children aged 6 to 59 months be considered a priority for influenza vaccination. The Advisory Committee on Vaccines and Immunizations of the Spanish Association of Pediatrics (CAV-AEP) recommended influenza vaccination for children and adolescents in 2008, initially as an individual recommendation and, since 2022, as a universal recommendation for children aged 6 to 59 months. In 2023, the Interterritorial Council of the Spanish National Health System supported this initiative, extending it to the entire country and incorporating it into the routine immunization schedule. The protective efficacy of the influenza vaccine in the pediatric population is higher than that observed in adults.

The Spanish Association of Pediatrics’ Advisory Committee on Vaccination (CAV-AEP) recommends, for the 2025-2026 influenza campaign, vaccination for all children between 6 and 17 years of age not included in at-risk groups, as it provides individual protection for the child and promotes family and community protection. Likewise, it recommends the preferential use of the live attenuated intranasal vaccine in children over 2 years of age (if there are no contraindications), due to its greater acceptability (it avoids the injection), its ability to facilitate and improve coverage, and its greater effectiveness after a single dose. Vaccination is also recommended, as an individual recommendation, for all at-risk groups from 6 months of age and adolescents in certain situations or with underlying health conditions that increase the risk of influenza complications(22).

The recommended dosage (number of doses) is: a) from 6 months to 8 years of age: a single dose, unless they belong to a risk group, in which case two doses will be given with a 4-week interval, if it is the first time they are vaccinated; and b) from 9 years of age and older: a single dose each season. The only accepted contraindications are being under 6 months of age; in this case, influenza vaccination should be recommended for pregnant women, and a severe prior allergy to the vaccine or to a component other than egg. An allergy to egg protein should not be considered an absolute contraindication to the influenza vaccine.

Inactivated vaccines should be administered by intramuscular or deep subcutaneous injection. For very young children who have not yet begun walking, the preferred injection site is the anterolateral aspect of the mid-thigh, and for older children, the deltoid muscle. Influenza vaccines can be administered concurrently with other inactivated vaccines, but at different anatomical sites. The intranasal live attenuated vaccine can be administered concurrently with other inactivated or live attenuated parenteral vaccines; no interval is necessary if they are not administered on the same day.

Finally, it should be remembered that the influenza vaccine generally has, especially the live attenuated vaccine for children, at least two important protective effects: a) it reduces susceptibility to influenza infection and disease in vaccinated individuals (efficacy versus susceptibility); and b) a decrease in infection has been partially demonstrated in other unvaccinated pediatric and non-pediatric populations, who exhibit lower infection rates when adolescents, and especially children under 5, are vaccinated. Therefore, vaccination of one population segment extends its effects to groups directly exposed to them (herd immunity or barrier immunity). In light of all the studies carried out in recent years, universal vaccination of the child population between 6 and 59 months seems logical, to protect this population directly, reduce or eliminate the transmissibility of the infection and indirectly obtain an important impact within the community, interrupting the chain of transmission of the flu virus to other more vulnerable groups, including adults.

Nevertheless, the primary motivation for influenza vaccination in children should be the individual well-being of the child and the reduction of the disease burden, with the benefits to the community derived from potential herd immunity taking a secondary role. The decision to vaccinate the child rests with the parents, and their acceptance will be influenced by key factors, such as trust in the pediatrician (active recommendation) and their attitude toward the vaccine, the effectiveness and types of vaccines available, fear of side effects, risk perception, and the parents’ own attitude toward influenza vaccination.

The main functions of pediatricians, regarding the flu vaccine, are: to evaluate the child’s vaccination needs based on age, possible underlying pathology and the social environment in which he/she lives.

Furthermore, after that assessment, indicate the best type of flu vaccine that meets the child´s flu protection needs.

After vaccination, the possible appearance of side effects should be monitored, which, although very rare, should be taken into account.

To evaluate the effectiveness of influenza vaccination throughout the flu epidemic of that season, assessing any respiratory conditions that may appear.

Conflict of interest

There is no conflict of interest in the preparation of this manuscript nor any source of funding.

The asterisks indicate the article’s level of interest in the author’s opinion.

1.* Reina J. La gripe humana. Human influenza. Rev Esp Virol. 2018; 21: 43-8.

2.* Ortiz de Lejarazu R. Los virus de la gripe. Pandemias, epidemias y vacunas. Influenza viruses. Pandemics, epidemics and vaccines. Amazing Books. 2019.

3. Neuzil KM, Zhu Y, Griffin MR, Edwards KM, Thompson JM, Tollefson S, et al. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis. 2002; 185: 147-52.

4. Reina J, Ballesteros F. La vacuna de la gripe en el nuevo milenio: perspectivas e indicaciones pediátricas. The flu vaccine in the new millennium: perspectives and pediatric indications. Rev Esp Pediatr. 1999; 55: 489-96.

5. Ortiz de Lejarazu R, Moraga-Llop F. Carga de gripe en la población pediátrica en España y los beneficios de la vacunación. Influenza burden in the pediatric population in Spain and the benefits of vaccination. Vacunas. 2023; 24: 95-121.

6. Nair H, Brooks WA, Katz N, Roca A, Berkley JA, Madhi SA, et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet. 2011; 378: 1917-30.

7. Peteranderl C, Herold S, Schmoldt C. Human influenza virus infections. Sem Respir Crit Care Med. 2016; 37: 487-500.

8.* Ortiz de Lejarazu R, Tamames S. Vacunación antigripal. Efectividad de las vacunas actuales y retos de futuro. Influenza vaccination. Effectiveness of current vaccines and future challenges. Enferm Infecc Microbiol Clin. 2015; 33: 480-90.

9. Reina J, Reina N. Vacunación antigripal universal: perspectivas de futuro. Universal influenza vaccination: future perspectives. Vacunas. 2019; 20: 72-81.

10. Reina J. Las vacunas cuatrivalentes frente a la gripe estacional. ¿Son la solución definitiva? Quadrivalent vaccines against seasonal influenza. Are they the definitive solution? Med Clin. 2014; 142: 366-7.

11. Reina J. Vacunas atenuadas (cold-adapted) de la gripe. Attenuated vaccines (cold-adapted) of influenza. Vacunas. 2002; 3: 51-61.

12. Beyer WE, Palache AM, de Jong JC, Osterhaus AD. Cold-adapted influenza vaccine versus inactivated vaccine. Systemic vaccine reactions, local and systemic, antibody response, and vaccine efficacy. S meta-analysis. Vaccine. 2002; 20: 1340-53.

13. Belshe RB, Mendelman PM, Treanor J, King J, Gruber WC, Piedra P, et al. The efficacy of live attenuated cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998; 338: 1405-12.

14. Jacobson RM, Poland CA. Universal vaccination of healthy children against influenza. A role for the cold-adapted intranasal influenza vaccine. Paediatr Drugs. 2002; 4: 65-71.

15. Reina J, Iglesias C. El papel del pecado antigénico original en la respuesta a la vacunación frente a la gripe. The role of original antigenic sin in the response to influenza vaccination. Vacunas. 2022; 23: 46-54.

16. Reina J. Las vacunas de la gripe basadas en las partículas virus-like obtenidas mediante sistemas de expresión génica en células de insectos. Flu vaccines based on virus particles-like obtained through gene expression systems in insect cells. Vacunas. 2012; 13: 64-8.

17. Lim CM, Komarasamy TV, Adnan NA, Radharkrisnan A, Balasubramaniam V. Recent advances, approaches and challenges in the development of universal influenza vaccines. Influenza Other Respir Viruses. 2024; 18: e13276.

18. Sun W, Luo T, Liu W, Li J. Progress in the development of universal influenza vaccines. Viruses. 2020; 12: 1033-43.

19. Reina J. La nueva generación de vacunas de ARN mensajero frente a la gripe. The new generation of messenger RNA vaccines against influenza. Enferm Infecc Microbiol Clin. 2023; 41: 301-4.

20. Arevalo CP, Bolton MJ, Le Sage N, Furey C, Muramatsu H, Alameh MG, et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science. 2022; 378: 899-904.

21. Gupta D, Mohan S. Influenza vaccine: a review on current scenario and future prospects. J Gen Enginn Biotech. 2023; 21: 154-63.

22. Comité Asesor de Vacunas e Inmunizaciones de la AEP. Vacunación frente a la gripe estacional en la infancia y la adolescencia. Recomendaciones 2025-2026. Spanish Association of Pediatrics (AEP) Advisory Committee on Vaccines and Immunizations. Seasonal influenza vaccination in childhood and adolescence. 2025-2026 recommendations. AEP (Internet). 2025. Available at:https://vacunasaep.org/documentos/recomendaciones-de-vacunacion-frente-la-gripe-2025-26.

23. Ortiz de Lejarazu R, Tamames S. Vacunas de gripe. Influenza vaccines. Pediatr Integral. 2020; 8: 469-78. Disponible en:https://www.pediatriaintegral.es/publicacion-2020-12/vacunas-de-gripe/.

Recommended bibliography

– Reina J. La gripe humana. Human influenza. Rev Esp Virol. 2018; 21: 43-8.

It presents a clear review of the epidemiology and clinical aspects of influenza and the biological characteristics of different influenza viruses, based on their biological behavior.

– Ortiz de Lejarazu R. Los virus de la gripe. Pandemias, epidemias y vacunas. Influenza viruses. Pandemics, epidemics and vaccines. Amazing Books. 2019.

This is a comprehensive book that covers all the general characteristics of influenza, influenza viruses, their epidemiology and diagnostic techniques as well as the updated therapies against this virus in 21 chapters.

– Ortiz de Lejarazu R, Tamames S. Vacunación antigripal. Efectividad de las vacunas actuales y retos de futuro. Influenza vaccination. Effectiveness of current vaccines and future challenges. Enferm Infecc Microbiol Clin. 2015; 33: 480-90.

Excellent review of existing flu vaccines, their virological basis, and prospects.

– Reina J. La nueva generación de vacunas de ARN mensajero frente a la gripe. The new generation of messenger RNA flu vaccines. Enferm Infecc Microbiol Clin. 2023; 41: 301-4.

Updated article on influenza vaccines based on messenger RNA platforms, which complements the previous review article.

A 3-year-old patient presented in January with an acute episode of cough, pharyngitis, malaise, myalgia, and nasal discharge of 48 hours’ duration, associated with a fever reaching 38.2°C in the last 12 hours. Physical examination revealed a good general condition, with no signs of respiratory distress or crackles. The pharynx was reddened and exudated. No lymphadenopathy was evident. The tympanic membranes were congested but not bulging. A throat aspirate was taken, and antigen detection for respiratory viruses was performed, which was positive for one of them. There is a family history of similar symptoms. The pediatrician recommends vaccination against this virus in the upcoming season.

Conclusión

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