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Live-attenuated influenza vaccine: Challenges to widespread use in children
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There are several challenges to implementing the live-attenuated, temperature-sensitive influenza vaccine (FluMist, MedImmune) in primary care offices. Many of these can be overcome. One of the biggest challenges in primary care private practice pediatrics is how to make a reasonable profit with live-attenuated influenza vaccine. This article will provide an update and financial challenges and some proposed solutions for live-attenuated influenza vaccine.
Managed care organizations will not revise their reimbursement schedules until an official recommendation for its use is published either in Morbidity and Mortality Weekly Report (MMWR) or, in some cases, by an official AAP publication. Last September, the FDA approved the vaccine for children as young as 2 years, followed two months later by publication in MMWR. On Feb. 27, 2008, the Advisory Committee on Immunization Practices voted unanimously that all children aged 6 months to 18 years be vaccinated for influenza every year. This recommendation may be acted on before the next influenza season and will likely require an upwards estimation of vaccine requirements for pediatric offices.
FluMist is a thimerosal/preservative-free, intranasally-administered influenza vaccine with a shelf-life of four months. It has already been in clinical use in pediatric offices for half a decade. The live-attenuated vaccine viruses are administered into the nasal vestibules in the form of a fine atomized mist. The live, but cold-adapted, modified trivalent influenza virus particles replicate only in the nasopharyngeal mucosa, where they are able to elicit host production of strain-specific immunoglobulin A and G antibodies. Attenuation of the influenza A and B subtypes is designed to prevent the virus from producing classic symptoms of the disease influenza. Because the attenuated influenza viruses are cold-adapted, temperature-sensitive genetically engineered strains, they cannot cause influenza disease. Attenuated vaccine-specific, temperature-sensitive influenza viruses can be shed for a median of 7.6 days after administration of LAIV-T; however, the amount of viral particles shed by vaccinated individuals is less than the calculated amount necessary to infect susceptible adults. In a Finnish day care study composed of infants aged 8 to 36 months, shedding of LAIV was estimated to be 0.58%.
In a randomized, double-masked, placebo-controlled investigational study conducted in children who were aged between 6 to 59 months during the 2004-2005 influenza season, there was a 55% reduction in cases of culture-confirmed influenza among the children who received LAIV-T. Data from another double-masked, placebo-controlled study showed that the LAIV demonstrated an overall reduction of 54% in influenza cases for children aged 6 and 59 months. Also in that study, LAIV resulted in 58% fewer cases of influenza disease that were due to mismatched strains. Adverse effects of LAIV were generally mild.
In response to a request for comments on use of LAIV-T in pediatric offices, postings on the AAP Section on Administration and Practice Management list-serv noted excellent acceptance by parents and children. Several respondents stated that they wished that their pediatric practice had ordered more LAIV-T because they quickly were depleted of this year’s procurement. In anticipation of the CDC approving the panel’s recommendation for universal influenza immunization, MedImmune plans to triple production of LAIV-T to about 12 million doses in time for the 2008-2009 influenza season.
Click on the image to view a full-size version.Problems and solutions
A short shelf life of four months is one challenge primary care physicians face in trying to routinely use this vaccine. There was an unanticipated delay in vaccine distribution in the late summer and early fall of 2007. Product that was first shipped to physician’s offices in October and November had an expiration date at the end of that year. Because of uncertainty about exact shipping dates and uncertainty about adequate reimbursement from managed care organizations, particularly for children aged 2 to 5 years, physicians were forced to immunize the majority of their patients with the TIV injectable vaccine. As a result, some physicians were “stuck” with an oversupply of LAIV-T, causing a financial loss.
Let lessons from the past be a guide for the future. Learn what managed care organizations will pay for LAIV-T product and for intranasal administration. Try to negotiate for better reimbursement to make a fair profit of at least $15 for product or consider the use of waivers, if legal in your state. Request a risk-sharing arrangement with the manufacturer for next year’s LAIV-T vaccine purchase.
Another challenge is parental belief that influenza vaccine is not important or that it is usually ineffective in preventing influenza because of antigenic shifts or drifts causing a major mismatch between the previous year’s choice of influenza subtypes and the next year’s novel influenza subtypes. Several widely-believed myths are additional barriers to parental acceptance of LAIV-T for their children. These include the belief that live genetically-modified vaccine virus can mutate and revert to wild-type influenza virus and cause a pandemic. This has never been demonstrated despite research attempts to document reversion to wild-virus.
Click on the image to view a full-size version.Teach parents that the burden of influenza is substantial on the family, school and community. Also, LAIV-T has demonstrated superior efficacy to TIV injection during years when there are mismatched strains.
Pediatricians also face the reality of inadequate reimbursements for LAIV-T, and many other vaccines, from major managed care organizations. This can cause a loss of income or a break-even return on investment for the vaccine. A minority of managed care organizations have the same reimbursement for LAIV-T as they do for TIV. Table 1 lists 2008 LAIV-T purchase price and managed care organizations reimbursement in the northeastern part of the United States.
According to expert recommendations from the AAP Section on Administration and Practice Management, pediatricians should insist on reimbursements that are 17% to 28% above average wholesale price on all vaccines. LAIV-T is a covered biological by more than 90% of managed care organizations; yet, it is inadequately reimbursed by most of them. Why is the administration fee for LAIV-T less than that for injectable vaccines?
In addition, the cost of LAIV-T has increased. In the fall of 2007, LAIV-T cost $17.95 per dose, compared with about $10 per dose of injectable TIV. For the 2008-2009 influenza vaccine administration months, MedImmune anticipates a $1 increase per dose for LAIV-T.
It is anticipated that more parents will insist on preservative-free influenza vaccines for the 2008-2009 influenza vaccine administration season. This precludes widespread use of multidose vials that cost less than pre-filled vials. This will narrow the price differential between LAIV-T and TIV products.
Competition from Wal-Mart and other discount pharmacy chains is another challenge. During the past two influenza seasons, most convenience clinics staffed by nurse practitioners would not administer injectable influenza vaccine to children aged younger than 12 years. This age restriction may vanish if LAIV-T is in widespread use at these immunization clinics.
Physicians should insist on early delivery of LAIV-T. Begin to immunize children in late summer. Aggressively market the fact that influenza immunizations have started. Consider immunization clinics at convenient times in the evenings and on weekends.
Another challenge is the percentage of children who are unable to receive LAIV-T because of true contraindications or perceived pseudo-contraindications that are really warnings or precautions. There are three contraindications at present:
- Administration of LAIV-T to children younger than 2 years.
- Administration of LAIV-T to children or adults who are allergic to chicken eggs or egg albumin, gentamicin, beef gelatine or to previous influenza vaccines.
- Administration of LAIV-T to children taking aspirin.
There are strong warnings or precautions against LAIV-T administration to children younger than 2 years and older children who have a history of recurrent wheezing, including severe bronchial asthma. Administration to patients with asthma is not currently recommended by the ACIP. According to the product insert, the physician should weigh the risk and benefits of administration of LAIV-T in individuals with mild to moderate bronchial asthma; recurrent wheezing in children aged 2 to 5 years, a past history of Guillian-Barré syndrome, and altered immuno-competence and high-risk underlying medical conditions. It should be noted that breast-feeding is not a contraindication for LAIV-T.
Conclusion
As stated above, live-attenuated, temperature-sensitive influenza vaccine contains no thimerosal or other preservative and does not require an injection to administer the product. Compared with trivalent, injectable influenza vaccine, it provides superior protection and longer duration of immunity from influenza A and B viruses, even when there is a mismatch between vaccine strains and the current influenza strains. There are several challenges to widespread use of this vaccine by primary care physicians. Many of these can be overcome.
For more information:
- Richard H. Schwartz is from the Department of Pediatrics at Nova-Fairfax Hospital for Children, Falls Church, Va.
- Belsche RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338:1405-1412.
- Belsche RB, Edwards KM, Vesikari T, CAIV-T Comparative Efficacy Study Group. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.
- Tosh PK, Boyce TG, Poland GA. Flu Myths: Dispelling the myths associated with live attenuated influenza vaccine. Mayo Clinic Proc. 2008;83:77-84.
- Redding G, Walker RE, Hessel C, et al. Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 2002;21:44-48.
- Vesikari T, Karvonen A, Korhonen T, et al. A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine. Pediatr Infect Dis J. 2006;25:590-595.