5 February 2023 Episode 313 Flu vaccination in children?

Episode 313:  Usefulness and risks of flu vaccination with focus on children?

Dear colleagues,

Don’t expect too much from this episode.  The title reflects a question, asked by someone amongst you, already a while ago.  I have been reading and pondering a lot, but I feel not qualified to defend a strong position.  His concern, as a pediatrician, was that indeed there is an ongoing debate for decades, which has led to different positions taken by US (CDC), European (ECDC) and Belgian authorities. 

In this mail, I will summarize the official recommendations and comment on the differences. For my own education, I have also collected illustrative papers and reviews on various aspects of Influenza, which are summarized in the attachment, with the papers as pdf on our website, as always:

Summary of Recommendations

Ep 313-1: CDC document 30 Nov 2022: “Flu Vaccines are important for children” is oriented towards a broad audience and contains an unambiguous message:

CDC recommends that everyone 6 months and older get a seasonal flu vaccine each year. Keep in mind that vaccination is especially important for certain people who are higher risk of developing serious flu complications or who are in close contact with people at higher risk. This includes children at higher risk of developing serious complications from flu illness, and adults who are close contacts of those children

Ep 313-2: ECDC scientific advice of Oct 2012 on seasonal influenza vaccination of children and pregnant women is the report of an expert panel (not oriented towards a broad audience).

1. Children 6 months to 18 years:

All experts present agreed that children aged six months to 18 years with underlying conditions should be vaccinated against seasonal influenza.

For “healthy” children no clear advice:

• The effectiveness of vaccines can differ between years because … the effectiveness of vaccines is partly dependent on the degree of matching between the predetermined influenza strain used in the vaccine and the circulating vaccine types.
• Even if an influenza vaccine is less effective than desired, vaccination is still the most effective preventive strategy for severe influenza; vaccination has also been shown to reduce hospitalization in children.
• Evidence on vaccine efficacy and effectiveness in children is limited. Data from available studies show an efficacy/effectiveness comparable to that in the elderly.

2. For children less than 6 months:

1. Vaccination of pregnant women: in favor

• If a woman is vaccinated during pregnancy, she is less likely to acquire influenza, which in turn reduces the chance of mother-to-child transmission after giving birth and during the first months of life.  The RCT conducted in Bangladesh showed indeed that influenza antibodies from the mother are transferred to the child.
• Vaccination during pregnancy is safe: there is reassuring evidence from the US, where two million pregnant women were vaccinated against influenza between 2000 and 2003, and only 20 adverse events were reported to vaccine-related. These included nine injection-site reactions and eight systemic reactions (e.g. fever, headache, and myalgias). In addition, three miscarriages were reported, but no causal relationship to vaccination54 has been established.
• No alternative: The use of antiviral therapy is not licensed in children younger than six months of age. The same applies to influenza vaccines. Therefore, there is a lack of alternatives to protect or treat children younger than six months against influenza, while the burden in this group is high.

Note: Effectiveness of vaccination to prevent hospitalization of pregnant women themselves:

During seasonal influenza is considered less convincing. 

• Some studies point to reduced disease burden, others fail to confirm it.
• Remarkably, one study found odds of hospitalization for respiratory conditions increased by trimester (from OR 1.4 in the second trimester to OR 4.7 in the third trimester).  
• Data from the Netherlands, however, indicate that an estimated 1500 healthy pregnant women would need to be vaccinated in order to prevent one hospital admission in this group due to seasonal influenza.

During the pandemic H1N1 influenza of 2009-2010, data from UK and New Zealand seem to indicate that there was an increased risk of complications for unvaccinated mothers and their newborns… 

2. Vaccination of contacts?: could theoretically reduce transmission, but evidence is lacking

Ep 313-3: ECDC flyer on Influenza 7 Nov 2022 oriented towards a broad audience

Considered as “high-risk” groups to suffer from severe illness:

• the elderly
• people of any age with chronic medical conditions (such as heart disease, those with lungs and airway problems and people suffering from diabetes or system problems),
• pregnant women, and
• children under five years.

Recommendation for vaccination:

EU Member States recommend the seasonal influenza vaccination for risk groups, such as

- older adults, with age ranging from ≥50 to ≥65 years, depending on the country,

- individuals with chronic medical conditions.

The World Health Organization (WHO) and the EU also recommend countries to improve vaccination coverage for healthcare workers.

Most EU Member States follow the WHO recommendations to vaccinate pregnant women,

and some follow recommendations to vaccinate healthy children aged 6 months - 5 years.

An update of seasonal influenza vaccines is needed yearly, since influenza viruses constantly evolve.

Ep 313-4:  Advice of the Belgian Superior Council (April 2022) ( A Dutch; B French, no English version)

 Category A:

- Group 1: persons at risk of complications, i.e.:

                    o all persons from the age of 65;

o all patients from 6 months of age suffering from an underlying disease chronic disease, even if stabilized, of the lungs (including severe asthma), the heart (excluding hypertension), the liver or the kidneys, to metabolic diseases (including diabetes), from neuromuscular disorders or from immune disorders (natural or induced) and persons with a Body Mass Index (BMI) > 35;

                    o persons residing in an institution;

                    o all pregnant women regardless of the phase of the pregnancy;

o children from 6 months to 18 years on long-term aspirin therapy*. 

- Group 2: persons working in the health sector, inside and outside healthcare institutions (interruption of transmission). The category “people active in the healthcare sector” contains all socio-professional categories listed in advice SHC 9611 of September 2020 were (Appendix 1)

- Group 3: persons living under the same roof (cocoon vaccination strategy) as

                    o the risk persons from group 1;

                    o children younger than 6 months.

Category B (50-65 years) and C (18-50): vaccine on individual basis

In an accompanying flyer  (Ep 313-4C) towards a broader audience, the High Council addresses mainly the 50-65 years old

Are you between 50 and 65 years old? Then discuss with your doctor whether a vaccination against seasonal flu is indicated for you, even if you do not necessarily suffer from a high-risk condition. Certain lifestyle habits also play an additional role in 1 in 3 people. Think about smoking, excessive alcohol consumption or an unhealthy diet.

With regard to the rest of the population, systematic vaccination is not recommended, although it is of course also possible no harm.

Clearly: healthy children between 6 months-18 years are not really discussed!

The hesitance in Belgium/Europe to advise vaccination in children may be because of an ongoing controversy on whether or not a “mismatch” vaccine could actually be ineffective or even enhance the chances of infection in children.

This is nicely explained in Ep 313-5: Geert and Isabel Leroux-Roels Vax Info.org 2018 on Effectiveness of repeated annual flu vaccination

They analyze several examples of a lower than expected protection or even an increased “flu attack rate” in children, who had been repeatedly vaccinated before with inactivated flu vaccine.    These phenomena were observed in a British boarding school in the seventies (https://www.ncbi.nlm.nih.gov/pubmed/83475), a household cohort in Michigan in 2010-2011 ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693492/)   but it was not confirmed in other studies in other time periods ( https://www.ncbi.nlm.nih.gov/pubmed/9269055 ) ( https://www.ncbi.nlm.nih.gov/pubmed/9796045)

In this paper, the paradox is explained by the “antigen distance hypothesis” , which is a variant of the “original antigenic sin” or “imprinting” hypotheses: a previous encounter.  Other terms such as “back boosting, negative interference and antigenic seniority” refer to the same phenomenon.

Clearly, the common theme is that a previous encounter with an antigen (infectious virus or vaccine) produces an imprint in the B (and T) cell immune memory. 

• Whenever the person is confronted with the same or a very similar virus again, this imprint is actually very beneficial, because (s)he will rapidly mount truly neutralizing antibodies and T cells, hence resulting in improved protection.
• However, when the virus has evolved escape mutations to the immune responses induced by previous variants (either as an infectious agent or as a vaccine), B cells (and maybe also T cells?) could be “deviated” towards the “old” (escaped) epitopes, resulting in no protection or probably even enhanced  disease as compared to the subjects who had not been exposed to the previous variant.

Clearly, encounters with either a previous infectious virus or vaccine can induce imprinting. Depending on the similarity between previous and actual encounter, imprinting can have a beneficial or a deleterious effect on a subsequent encounter with a next infectious influenza virus.

At present, it remains difficult to accurately predict the antigenic characteristics of the next seasonal Influenza virus, it is not excluded that a previous vaccination (even several years before) can have a negative influence, but that also applies to a previous infection.  Obviously, as we also learned from COVID, an “infectious encounter” induces a broader and more powerful immune response, but at the price of a risk for severe disease.

On a subjective note, I’m certainly in favor of flu vaccination in children, because the worse disease I survived until now, was a serious flu at age 9-10, while I didn’t have any risk factor…. But in all objectivity, it is not sure if the “traditional egg-based inactivated” flu vaccines are really protective enough for that age group. And, as you will see in the attachment, the intranasal attenuated vaccine fails to perform better, despite theoretical advantages. Therefore, “the jury is still out” on whether as of today, healthy children should be vaccinated against influenza. 

There is, however, a realistic hope that flu vaccines will improve in the near future, both with regard to the antigenic specificity and with regard to the “breath” and “depth” of immune responses (e.g. activation of T cell responses and anticipating on new escape mutations). 

Please find some “didactic” (but very incomplete) background in attachment.

Looking forward to your comments, suggestions in this longstanding debate.

Best wishes,

Guido

Note: * The contraindication of influenza vaccination in children with chronic aspirin therapy, is because of a possible association of aspirin intake and Reye’s syndrome (https://www.ninds.nih.gov/health-information/disorders/reyes-syndrome). 

However, here also, there seems a difference between Europe and US, as the American Heart Association clearly states: All children ≥6 months should receive a seasonal influenza vaccine, as should their family members. Only inactivated vaccine should be administered to children on aspirin therapy.  

See Ep 313-34 AHA Recommendation p. 19.