Pharmacy and Therapeutics - January 2008 - (Page 37) Advances in Vaccine Technology Clinical trials of GSK’s VLP-based HPV vaccine Cervarix have shown similar cross-protective responses to subtypes not included in the vaccine, which might be attributable to the novel adjuvant ASO4.21,24,25 The ability of certain adjuvants to enhance the levels of memory B cells and antibodies, in some cases to numbers much higher than those seen with natural infection,26 has implications for the longevity of the response as well. In one study comparing ASO4 plus alum with alum alone against HPV, significantly higher antibody titers were observed when ASO4 was included.26 This advantage was maintained during long-term follow-up. These dual benefits—extending the time that antibody levels are maintained above the threshold required for neutralization of the organism and enhancing the capacity of the patient to respond to a booster immunization—are important for future planning and estimating costs. However, we need to better define the correlates of immunity for specific vaccines. The threshold necessary for neutralization differs among various organisms; knowing this parameter and other related measures is desirable and sometimes necessary. Advances in vaccine technology necessitate concomitant advances in vaccine immunology. Considering the rising costs of research and development, another desirable feature of adjuvants is their ability to be paired with multiple antigens so that they can be included in different vaccines. For example, ASO4 has been studied in conjunction with both hepatitis B and HPV vaccines.26 This capability can reduce the vaccine’s developmental costs and the time to market. With each new adjuvant and each new combination of adjuvant and vaccine, the advantages of increased immunogenicity, longevity, and perhaps broadened coverage of strains must be balanced with the potential for increased reactogenicity. In this context, reactogenicity refers to the generally undesirable effects of the vaccine, typically mediated by the immune response to the vaccine rather than by the product’s direct toxicological effects. Redness or swelling at an injection site are two common examples. Despite this rapid technical progress, vaccines were not on the “radar screen” for managed care before some of the recent product launches. Previously, the extent of managed care’s involvement was limited to assisting in acquiring supplies for some integrated systems, working with quality on Health Plan Employer Data and Information Set (HEDIS) measures, and participating in clinics and health fairs. However, the advent of newer vaccines that target diseases causing morbidity rather than mortality in the U.S. (e.g., rotavirus or herpes zoster) is encouraging MCOs to perform more clinical and economic analyses in order to ensure that their investments in vaccination are being maximized. The entry of the live attenuated influenza vaccine FluMist (MedImmune) into the market in 2004 and the anticipated introduction of a second HPV vaccine (Cervarix, GSK) present new challenges. These products target essentially the same disease processes as those targeted by vaccines already approved, but they differ in their approach and, potentially, in their clinical effectiveness. The availability of similar products is relatively new in the world of vaccines, and MCOs will have to evaluate them closely in terms of their ef ficacy, safety, and economic impact. For example, the question confronting MCOs, in view of the HPV vaccine (Gardasil), as well as ASO4, and MF59, is whether the potential of lower reactogenicity from an established adjuvant is more important than the potential for a stronger and possibly more durable immunogenic response. Ultimately, we might simply derive the answer if we know which product provides better protection against the HPV types most commonly linked to cervical cancer in a cost-effective manner. These types of analyses place a greater value on cost-effectiveness, clinical, and budget-impact data for the newer vaccines— data that have been lacking in the past. Although short-term benefits offer immediate returns to MCOs, it would be irresponsible for these health plans to focus exclusively on these benefits and deny coverage of vaccines in an effort to save money. Such restrictions place the broader population at risk, and they may have the unintended consequence of damaging a company’s reputation. Further, a focus on short-term benefits puts health plans at a disadvantage in terms of competing for participants during enrollment; most plans offer broad vaccine coverage, although there might be restrictions based on product labels, guidelines, or age limitations. Another way to increase the value of future vaccines would be to quantify both the possible short-term and long-term cost offsets attributable to the availability of the specific product. Again, because it is crucial that MCOs not waste money, the emphasis should be on outcomes and cost-effectiveness. In concert with the advances in vaccine engineering and adjuvantation, novel routes of delivery are also being investigated. Intradermal delivery directly to an environment rich in antigen-presenting cells (APCs) is considered to be a dose-sparing measure for several vaccines, including those used for HIV and influenza.27 Needle-free variants of this route, such as transdermal patches and electroporation, are also being tested for conditions as diverse as influenza, traveler’s diarrhea, and melanoma.12,28,29 Mucosal delivery, which has the advantage of not requiring a needle, is already being used for several vaccines. The live, attenuated influenza vaccine FluMist is given as a nasal spray, and the rotavirus vaccine, licensed in the U.S in 2006, is delivered orally.30,31 The mucosal route of delivery may contribute to the heterovariant cross-protection seen with both of these vaccines by inducing broader immunity, including mucosal immunoglobulin A. Mucosal delivery is also being studied for several other potential vaccines directed against diseases such as HIV infection and tuberculosis.12 In the past, MCOs tended not to pay a premium for convenience alone. If an alternative (needle-free) route of delivery is associated with improved outcomes, such a premium might be worth the additional investment. The demand for vaccines by employers and physicians is also an important consideration. Individual health plan members and small employers might be less willing to cover the cost of new vaccines because of the possibly significant impact on premiums. Small employers with a pool of healthy young employees might not be interested in covering vaccines for disease states with poorly documented short-term benefits. With the arrival of many new biologic agents and vaccines, Vol. 33 No. 1 • January 2008 • P&T® 37
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