New LAV Vaccination Strategies
In the 1980s, there was an attempt to increase seroconversion rates upon LAV vaccination by increasing vaccine potency. However, immunization with these so-called ‘high-titer measles vaccines' was associated with a poorly understood increase in mortality in girls later in life when compared with children vaccinated with the standard vaccine.[24–26] Consequently, the WHO advised discontinuation of this strategy. Recent studies have suggested that the observations may have been caused by changes in the sequence of administration of childhood vaccines rather than the LAV titer. Currently, clinical research is mainly focusing on changing the route of administration of LAV.
A promising alternative route for the administration of LAV is aerosol inhalation, either as nebulized vaccine or as a dry powder. This approach bypasses the need for syringes and professional healthcare workers, could lead to better immunity at the site of entry and was suggested to be capable of inducing protective immunity in the presence of maternal antibodies.[28,29] The use of dry powder might even be more beneficial, since it could further reduce the need for cold-chain maintenance.
Numerous clinical trials with aerosolized measles vaccine have been performed, but only a few in infants without pre-existing immunity against measles Table 1 . The first clinical trials were performed in Mexico and demonstrated the feasibility of the aerosol route for measles vaccination.[28,31–33] In subsequent years, vaccination studies were performed mainly in infants below 9 months of age, in whom subcutaneous injection proved to be more effective than aerosol inhalation.[34–37] More recently, Wong-Chew et al. reported that primary aerosol vaccination induced good humoral and cellular immune responses in children of 12 months of age, albeit not as efficient as subcutaneous vaccination. In 2006, the same group reported that, in children of 9 months of age, aerosol vaccination performed dramatically worse compared with subcutaneous vaccination. However, the authors suggested that these differences could be attributed to technical limitations of aerosol administration. Recent meta-analyses have also revealed varying results. One study reports no significant difference between primary aerosol and subcutaneous immunization. A more recent meta-analysis reported that in children below 10 months of age, subcutaneous vaccination is more effective, at 10–35 months, results are comparable and in older individuals aerosol is more effective. This would be in contrast to results from the 1980s, which suggest that aerosol is capable of inducing humoral immune responses even in the presence of maternal antibodies. However, this meta-analysis included the study of Wong-Chew et al. mentioned above, attributing the failure below 10 months of age to technical difficulties. All other studies included for this age group showed less dramatic differences between aerosol and subcutaneous vaccination.
Several studies have reported that the use of aerosol as a booster vaccination is beneficial. Better seroconversion rates were observed with aerosol as a booster after subcutaneous vaccination or natural infection when compared with a subcutaneous booster vaccination.[42–45] The same results were reported with a bivalent measles–rubella vaccine, and a trivalent measles–mumps–rubella vaccine. The last study reported some adverse events but these were attributed to the mumps component of the vaccine. One long-term follow-up study was performed comparing aerosol and subcutaneous booster vaccinations, and showed that 6 years after revaccination seropositivity was higher in the aerosol group compared with the subcutaneous groups. These studies indicate that aerosol can be efficiently used as a booster vaccination in individuals with pre-existing immunity.
Regulatory authorities consider a vaccine and its route of administration as one entity. As a consequence, preclinical and clinical studies were required to achieve licensure for this vaccination strategy. As part of the preclinical evaluation, we have recently compared administration of LAV strain Edmonston-Zagreb via aerosol, dry powder and injection in a macaque model. Aerosol vaccination induced similar levels of neutralizing antibodies and T-cell responses to the injection group, and protection from challenge infection with wild-type MV was comparable. Dry-powder aerosol vaccination proved to be less effective than injection in this study. This was attributed to formulation and administration of the vaccine, since the powder was deposited mainly in the upper respiratory tract. In addition, in vivo reconstitution of LAV in mucus or surfactant could pose a potential problem. New dry-powder formulations are currently under evaluation.
Since inhalation of LAV is associated with a number of theoretical safety risks, including the potentially increased risk of vaccine-induced pneumonia or encephalitis, aerosol vaccination was also tested for safety in immunosuppressed macaques, in which no significant lung or brain pathology was observed. However, these studies were performed in limited numbers of animals and additional safety data will need to be obtained in clinical trials and postlicensure evaluation. These studies will also need to evaluate the possible interference of concurrent respiratory tract infections with the efficacy of measles vaccination via the aerosol route.
Expert Rev Vaccines. 2008;7(8):1215-1223. © 2008 Expert Reviews Ltd.
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Cite this: Measles Vaccination: New Strategies and Formulations - Medscape - Oct 01, 2008.