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Saad B Omer a b c , Girish S Hiremath d, Neal A Halsey e
With 279 000 reported cases and 197 000 deaths per year, measles continues to be an important cause of childhood morbidity and mortality, especially in low-income countries.1 In 2008, the World Health Assembly reaffirmed the goal to reduce mortality from measles by more than 90% in 2010, compared with rates from 2000.2 Moreover, WHO's executive board has instructed its organisation to explore the feasibility of global measles elimination. Programmatic and technological innovation will be needed to sustain recent successes in reduction of the global burden of measles.
Delivery of the measles vaccine through the respiratory tract could help this effort. Respiratory delivery generates robust local and systemic immune responses3, 4 and this route is better for boosting responses in seropositive people than are injectable vaccines.5 Furthermore, mucosal administration is less likely to be blocked by maternal antibodies in infants than is a subcutaneous measles vaccine.6 Administration of aerosol vaccines needs fewer skills than does administration of injectable vaccines. Furthermore, use of non-injectable vaccines reduces the likelihood of unsafe disposal and reuse of syringes in immunisation programmes.
The idea to use the respiratory tract for delivery of measles vaccine is not new. Sabin7 suggested use of aerosolised measles vaccines in mass campaigns, and contributed to the design of an early aerosol vaccine delivery device, generally known as the classic Mexican device. The device is a plastic nebuliser containing reconstituted vaccine that is placed in crushed ice, and a connected compressor that generates the aerosols. Early designs of this device had several limitations, including the need for crushed ice and electrical power to run the compressor, a poor understanding of the correct dose for different ages, and the potential for transmission of respiratory pathogens.
In our meta-analysis8 of 20 reported comparisons from 16 studies, we reported that measles vaccines delivered through the respiratory route were at least as immunogenic as the same vaccine delivered subcutaneously. In another meta-analysis by Low and co-workers,9 children aged 10—36 months who were given aerosolised measles vaccine had seroconversion rates similar to children in the same age-group who received the vaccine subcutaneously. In infants younger than 10 months and children aged 5—15 years, results of studies were heterogeneous; therefore, seroconversion data were not pooled in this meta-analysis.9 Neither of these meta-analyses presented pooled safety data because of the inconsistent definitions of adverse events that were used in individual studies. However, the studies did not report any substantial differences in rates of serious adverse events between recipients given measles vaccines through the respiratory route versus the subcutaneous route.8, 9
With improvements in vaccine-delivery technology and progress in overcoming shortcomings of early devices, interest in respiratory delivery of measles vaccines has increased in recent years. Several groups10 are investigating methods of respiratory delivery of measles vaccines, such as nasal sprays, dry powders, and jet and piezoelectric (or mesh) nebulisers. Some development activities are being coordinated by WHO's Measles Aerosol Project, which aims to license at least one respiratory method to deliver vaccines that are administered subcutaneously.10 Products developed through this process will be used for routine immunisation of children aged 12—59 months and for mass immunisation of those aged 9 months to 18 years.11 The WHO project is investigating at least three methods for delivery of reconstituted aerosol measles vaccine.10 A device that uses dry-powder vaccine might also be assessed. Clinical trials10 are underway in India and Mexico to investigate the immunogenicity and safety of vaccine delivered through these devices, and at least one of these devices might be ready to be licensed in India by 2011.
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Despite much progress towards a deployable and safe method to deliver aerosolised measles vaccine, substantial challenges remain. Assessment of safety is one such challenge—especially in some high-risk groups, including children with asthma and immunocompromised children, such as those with HIV. Although parents in many populations might prefer the respiratory route instead of the subcutaneous route of measles vaccine administration, the acceptability of aerosol vaccines cannot be taken for granted. For example, uptake rates of the intranasal influenza vaccine have been lower than were expected.12 Moreover, most assessments of aerosol measles vaccines have been based on immunogenicity-related endpoints with only a small amount of data about clinical effectiveness, mostly outbreak-related data from Mexico.13 Randomised trials with disease-related endpoints, or at least studies of post-licensure field effectiveness, will be needed to assess the use and safety of respiratory measles vaccines.
SBO has received an award from the National Foundation of Infectious Diseases; GSH declares that he has no conflicts of interest; and NAH has received grants from GlaxoSmithKline and Merck, honoraria from Merieux and the National Foundation for Infectious Diseases, a travel grant from Sanofi Pasteur, and has served on data and safety monitoring boards for Merck and Novartis. SBO's work on this Comment was in part supported by the Emory University, Global Health Institute Faculty of Distinction Fund award. We thank Deanna West-Tankoo for her help with administration and retrieving relevant articles.
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a Hubert Department of Global Health, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA
b Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
c Emory Vaccine Center, Atlanta, GA, USA
d INOVA Fairfax Hospital for Children, Fairfax, VA, USA
e Department of International Health and Institute for Vaccine Safety, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA