The 2020/2021 autumn/winter season presents a significant challenge to the delivery of healthcare services, both in primary care and in hospitals, especially with a resurgence of cases of Covid-19 occurring at the time of writing. At an individual level, the consequences of dual infection with Covid-19 and other winter illnesses such as influenza and pneumococcal infection are unclear, but worse outcomes are likely in such scenarios, particularly for those at risk. 

As we head into the winter months, vaccination programmes in general practice related to influenza and pneumococcal infection have more significance than ever before. 

Influenza causes 200-500 deaths in Ireland each autumn and winter. Thousands need hospital admission, placing a considerable burden on our healthcare system. Pneumococcal infection is also a leading cause of death.

Pneumococcal infection

Mortality is highest in those who develop sepsis or meningitis. Infection can occur at any time throughout the year but rates peak during the winter months.

According to the RCPI Immunisation Guidelines for Ireland from the National Advisory Committee (NIAC),¹ pneumococcal meningitis case fatality rates of 11-16% were reported in Ireland between 2008-2016. Each year the age-specific incidence rates are highest among the elderly and young children. A decline in incidence in the young age groups has been evident in recent years as immunisation was introduced into the primary schedule in 2008.

Streptococcus pneumoniae (S. pneumoniae, pneumococcus) is an important cause of serious infection, especially in young children, older adults and immunocompromised patients. Transmission is from person to person by droplet infection or direct contact with respiratory secretions of someone carrying the organism. For pneumococcal infections, the incubation period is thought to be around one to three days.

Although more than 90 polysaccharide capsular serotypes of pneumococci are known, most infections are caused by a limited number of serotypes. The fact that relatively few serotypes cause most invasive disease has aided the development of effective vaccines.

The vaccine 

The pneumococcal polysaccharide vaccine (PPV23) contains purified capsular polysaccharide from 23 capsular types of pneumococcus which account for up to 90% of invasive pneumococcal disease (IPD).

Recommendations

NIAC advises that the following people who are in an at- risk group for pneumococcal disease should receive the PPV23 vaccine to provide protection from IPD.

At-risk groups:

• Everybody aged 65 years and over
• Everybody aged two years or older with the following:

– Diabetes

– Chronic lung, heart, liver, or kidney disease

– Chronic neurological disease 

– Children aged over two years and under five years of age with a history of invasive pneumococcal disease

– Coeliac disease 

– Down’s Syndrome

– Cochlear implants or are about to get cochlear implants 

– Immune deficiency because of a disease or treatment, including cancer patients

– HIV infection 

– Absent spleen or a non-functioning spleen

– CSF leaks, either congenital or complicating skull fractures or neurosurgery

– Intracranial shunt

– Occupational exposure to metal fumes (ie. welders)

– Smokers and people with alcohol dependence.

PPV23 vaccine is funded by the Department of Health and provided by the HSE for the majority of these risk groups. Please see www.immunisation.ie for details of the HSE programme. 

PPV23 vaccination is not recommended for healthy children and younger adults as they are at low risk of invasive pneumococcal disease.

Doses of PPV23 vaccine required for patients at risk 

All adults aged 65 years and older who have never previously received PPV23 vaccine require one dose only. No further doses are required regardless of immune status. 

The PPV23 vaccine can be given at the same time as any flu vaccine.

People under 65 years need one dose of PPV23 vaccine. These patients are also recommended to have a second dose of PPV23 vaccine when they reach 65 years of age, once five years has passed from the initial PPV23 vaccination. 

However, there are specific groups of patients in whom the response to the vaccine is expected to decline rapidly eg. those with no spleen or with splenic dysfunction, with immunosuppression including HIV infection, nephrotic syndrome, a renal transplant or chronic renal disease. These patients, if they are under 65 years of age, need one booster PPV23 vaccine after five years.

These patients, like all adults, are also recommended PPV23 vaccine when they reach 65 years of age once a five years interval from the second PPV23 vaccine has passed. So these patients require three PPV23 vaccines in total.

The PPV23 is not recommended every five years for any patient. See algorithm in Figure 1 for details.

Some patients at high risk of invasive pneumococcal disease are also recommended the PCV13 vaccine. PCV13 vaccine should always be given first followed by PPV23 vaccine after a time interval of two months to provide maximum immunological efficacy. However, if the PPV23 vaccine is given first, the PCV13 vaccine should not be given for an interval of one year to achieve maximum efficacy for both vaccines.

Managing outbreaks of pneumococcal disease

Any case of invasive pneumococcal infection or lobar pneumonia believed to be due to S. pneumoniae is managed by the public health consultant. They will review the patient’s history to establish whether they are in a risk group and have been vaccinated. Unvaccinated at-risk patients will be offered pneumococcal vaccine. 

All children under five years of age who have had IPD, even if not in a clinical risk group, should receive a dose of PCV13 irrespective of vaccine history, followed by a dose of PPV23 two months later (at or after two years of age). Antibiotic prophylaxis is not indicated for close contacts of a case of invasive pneumococcal disease as such contacts are not normally at increased risk of pneumococcal infection. 

Clusters of invasive pneumococcal disease should be discussed with local public health specialists. Outbreaks of pneumococcal infection in institutional settings need prompt investigation. 

Control measures, including vaccination, may be appropriate in some cases and should be discussed with the regional public health department.

More information is also available from the Royal College of Physicians of Ireland Immunisation Guidelines for Ireland Pneumococcal Infection (Chapter 16): www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/chapter16.pdf

Flu vaccination: new recommendations

To prevent cases of influenza in children and reduce the spread of influenza to others, NIAC has now recommended influenza vaccine for all children (aged 2-17 years inclusive).²

For the 2020/21 influenza season, the Department of Health, on NIAC advice, is extending the influenza vaccination programme and has provided funding to the HSE to offer quadrivalent live attenuated influenza (LAIV) vaccine free to all children aged two to 12 years inclusive.³

The aim of the extension of the influenza vaccination programme to children is to reduce: 

• Morbidity and mortality from influenza in children 
• The number of people with influenza
• The number of hospital admissions
• Transmission of influenza to the elderly and persons in risk groups 
• Transmission to healthcare workers in families with children
• Absenteeism of children from school and their parents from work.

The Department of Health has also provided funding to the HSE to provide administration of quadrivalent inactivated influenza vaccine (QIV) free to all in at-risk groups, regardless of medical card or GP visit card status. This includes all those aged 65 years and over, children aged 2-12 years, pregnant women, children aged 6-23 months and those aged 13-64 with long-term medical conditions, healthcare workers and carers.

Influenza in children

Children are among the most susceptible to influenza infection. It is estimated that 20-30% of children develop influenza during each influenza season compared to 5-10% of adults.⁴ Children, because they have limited pre-existing immunity, are primary vectors of influenza transmission in the community and shed the virus at higher viral titres. Children transmit the influenza virus for a longer period than adults; they can transmit the influenza virus for 10 or more days, compared to six days in adults, therefore increasing the spread of the disease. 

Approximately 10% of children under 15 attend their GP with influenza in an average influenza season. Influenza is an important cause of pneumonia, bronchitis, otitis media, croup and bronchiolitis in children. Incidence rates are highest in the younger age groups leading to high rates of excess outpatient visits, hospital admissions and antibiotic prescriptions. 

In Ireland during the 2018/2019 influenza season, 1,245 children were hospitalised with influenza.⁵ Children aged less than five years had the second highest hospitalisation rates for influenza after those aged 65 years and older. Between the 2009/10 and 2018/19 influenza seasons, some 4,750 children aged 0-14 required hospitalisation as a result of influenza, including 183 requiring critical care. Sadly, 41 children have died. 

Two influenza vaccines will be used in the 2020/2021 seasonal influenza campaign. 

Both vaccines contain the following four vaccine virus strains as recommended by the World Health Organization: 

• An A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus 
• An A/Hong Kong/2671/2019 (H3N2)-like virus
• A B/Washington/02/2019 (B/Victoria lineage)-like virus
• A B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.

The vaccines are:

Quadrivalent influenza vaccine [Split Virion, inactivated] (QIV), also marketed as Vaxigrip Tetra. It will be offered to all those in at-risk groups aged from 6-23 months and for those who are at-risk aged more than 12 years, including those aged 65 years and older, pregnant women and healthcare workers. This vaccine was used in the 2019/2020 influenza season.

Quadrivalent live attenuated influenza vaccine (LAIV) Fluenz Tetra will be offered to all children aged 2-12 years. It is administered intra-nasally. Trivalent LAIV was first licensed in the US in 2003 and trivalent LAIV was licensed in 2011 for children aged 2-17 years in Europe. In Europe, Quadrivalent LAIV has been licensed since 2012.

LAIV may contain residues of egg proteins (ovalbumin)  – maximum amount of less than 0.024µg and gentamicin. LAIV does not contain thiomersal or latex.

LAIV has a very short shelf life of 18 weeks. The expiry date must be checked before administration.

The expiry date is written on the side of the nasal applicator as a day, month and year and is the last date the vaccine can be administered

Influenza season 2020/21

Nine European countries, the US, Canada and Australia recommend influenza vaccine for children. The UK gives LAIV to children. Finland, the US and Canada give LAIV or QIV to children.^6,7,8 In Ireland, for the 2020/21 influenza season, vaccination of children will help minimise the burden of influenza by preventing influenza in children and the transmission of influenza from children to those in at-risk groups. This should reduce morbidity from influenza as well as influenza-related hospital admissions in all the at-risk groups. 

This is especially important this coming influenza season  in order to minimise the impact on our health services from the threat of dual outbreaks of influenza and a resurgence of Covid-19.

Most of those most vulnerable to influenza are also most vulnerable to Covid-19. Patients with influenza and Covid-19 co-infection are likely to have worse outcomes.

LAIV effectiveness 

Since LAIV contains live attenuated viruses, it mimics natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibodies, inducing more durable immune memory and so providing better long-term protection to children than inactivated influenza vaccines such as QIV. 

In some studies, LAIV has been shown to be more effective in children compared to inactivated influenza vaccines. In addition, LAIV may offer some protection against strains not contained in the vaccine, as well as virus strains that have undergone antigenic drift. 

A recent meta-analysis of LAIV suggested an efficacy against confirmed disease of 83% (95% confidence interval 69-91%).⁹

The UK pilot primary school programme introducing LAIV was evaluated in 2014/2015 and showed:¹⁰

94% reduction in primary school age children GP influenza-like consultations 

74% reduction in primary school age emergency department attendances with respiratory complaints 

93% reduction in primary school age-confirmed influenza hospitalisations 

59% reduction in adult GP influenza-like illness consultations.

LAIV dose and administration

Each LAIV vaccine comes as a prefilled nasal applicator and each applicator contains 0.2ml nasal suspension. The vaccine is administered by the nasal route. One dose of LAIV is 0.2ml administered in divided doses into each nostril, ie. 0.1ml in each nostril.

If the child’s nose drips after vaccination, the vaccine dose not need to be repeated. The vaccine is immediately absorbed after administration. Parents and guardians should be reassured the vaccine is still effective if this occurs. For the same reason, the vaccine does not need to be repeated if the child sneezes or blows their nose after vaccination.

LAIV can be given together with or at any time before or after the administration of any other live attenuated (eg. MMR) or inactivated vaccines.

NIAC has recommended healthy children require one dose of LAIV. However, children in a medically at-risk group aged two to eight years inclusive are recommended two doses of LAIV if they have never had any influenza vaccine before. The two doses should be given four weeks apart. 

Contraindications to LAIV:

Anaphylaxis following a previous dose of influenza vaccine or any of its constituents (other than ovalbumin – see Precautions; details of constituents can be found in the Summary of Medicinal Products and Characteristics (SmPC) available from www.hpra.ie

• Asthma

– Acute exacerbation of symptoms: increased wheezing and/or additional bronchodilator treatment in the previous 72 hours 

– Seek specialist advice if on regular oral steroids or previous ICU admission

• Significant immunosuppression due to disease or treatment
• Children who live with severely immunosuppressed persons (eg. post-haematopoietic stem cell transplant)
• Concomitant use of aspirin/salicylates 
• Influenza antiviral medication within the previous 48 hours 
• Those with severe neutropenia (absolute neutrophil count < 0.5 × 109/L) to avoid an acute vaccine related febrile episode
• Those on combination checkpoint inhibitors (eg. ipilimumab plus nivolumab) because of a potential association with immune-related adverse reactions.

The following are NOT contraindications:

• Asymptomatic HIV infection
• Children receiving: 

– Topical or inhaled corticosteroids

– Low dose systemic corticosteroids

– Replacement therapy corticosteroids (eg. adrenal insufficiency).

Precautions

Defer until recovered from an acute severe febrile illness. As LAIV has an ovalbumin content < 0.1µg per dose, it can be given to children with confirmed egg anaphylaxis or egg allergy in a primary care setting, except children who have required ICU admission to hospital for a previous severe anaphylaxis to egg, who should be given LAIV in hospital. 

Aspirin/salicylates should not be used for four weeks after vaccination unless medically indicated, as Reye’s syndrome has been reported following the use of salicylates during wild-type influenza infection.

Avoid influenza antiviral medication for two weeks post-vaccination.

Children aged two to 12 years for whom LAIV is contraindicated should be offered QIV (provided there are no contraindications to QIV).

Gelatin in LAIV 

LAIV, like some other vaccines, contains gelatin derived from pork, which is highly purified and hydrolysed and acts as a stabiliser. Gelatin in vaccines may cause concern to some members of the Muslim community. The National Immunisation Office has received a statement from the Chair of the Irish Council of Imams stating that vaccines containing gelatin are permitted. See www.immunisation.ie for further details. 

LAIV side-effects

Very common or common (more than 1 in 10 to 1 in 100):                                                                                                       Nasal congestion/rhinorrhoea; decreased appetite; malaise; fever; headache; and myalgia. In post-marketing surveillance, overall rates of fever were similar to the rates following other childhood vaccines and were generally mild and of short duration.

Very rare (less than 1 in 10,000): Immediate allergic reactions. 

Very rare cases of Guillain-Barré syndrome (GBS) have been observed in the post-marketing setting following influenza vaccination. The risk of GBS following influenza infection is significantly greater than that following influenza vaccination.

Can LAIV vaccine cause virus shedding?

The attenuated vaccine viruses in LAIV are cold-adapted. They can replicate at the lower temperatures found in the nose but cannot replicate efficiently at body temperature elsewhere in the body.

Vaccinated children can shed the attenuated virus for a few days after vaccination but the virus that is shed cannot cause infection. 

Role of GPs in promoting vaccination

Research, both in Ireland and elsewhere, has consistently shown that doctors and other healthcare professionals are the most trusted sources of information on vaccination. A recommendation by a trusted healthcare professional has been shown to increase vaccine uptake. 

Reminders to patients about vaccination have also been shown to increase vaccine uptake, be that by text, phone, email or letter.  

This influenza season, your recommendation to parents of children and others in at risk groups to get the influenza vaccine will be even more important, in order to maximise uptake. 

The National Immunisation Office has developed an LAIV vaccine e-learning module for vaccinators. This is now available at www.HSELand.ie

The NIO is producing information materials on LAIV for parents and for vaccinators and copies will be distributed to vaccinators with additional copies available to order. 

The introduction of LAIV vaccine will be accompanied by a public awareness campaign to inform parents about the benefits of universal influenza vaccination for children aged 2-12 years. 

References

1. Royal College of Physicians of Ireland Immunisation Guidelines for Ireland. https://www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/
2. RCPI Guidelines. Influenza Chapter https://www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/chapter11.pdf
3. Seasonal Influenza Programme 2020/2021 https://www.hse.ie/eng/health/immunisation/hcpinfo/fluinfo/
4. Antonova EA, Rycroft CE, et al. Burden of paediatric influenza in Western Europe: a systematic review Antonova. BMC Public Health  12, Article number: 968 (2012)
5. Health Protection Surveillance Centre (HPSC) Annual Epidemiological Report , Influenza and Other Seasonal Respiratory Viruses in Ireland, 2018/2019  (December 2019),  https://www.hpsc.ie/a-z/respiratory/influenza/seasonalinfluenza/surveillance/influenzasurveillancereports/previousinfluenzaseasonssurveillancereports/20182019season/Influenza%202018-2019%20Season_Summary.pdf
6. The NHS national flu immunisation programme 2020/21.https://www.england.nhs.uk/wp-content/uploads/2020/05/national-flu-immunisation-programme-2020-2021.pdf
7. Finnish Institute for health and welfare. Vaccination programme for children and adolescents [online]. Available from: https://thl.fi/en/web/vaccination/national-vaccination-programme/vaccinationprogramme-for-children-and-adolescents
8. Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2020–2021 https://www.canada.ca/en/public-health/services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2020-2021.html#I1
9. Caspard H, Mallory RM, Yu J, Ambrose CS. Live-Attenuated Influenza Vaccine Effectiveness in Children from 2009 to 2015–2016: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2017; 4(3): ofx111
10. Pebody RG, Green HK, Andrews N, et al. Uptake and impact of vaccinating school age children against influenza during a season with circulation of drifted influenza A and B strains, England, 2014/15  Surveillance and outbreak report https://www.eurosurveillance.org/images/dynamic/EE/V20N39/art21256.pdf