Needle-free delivery of measles virus vaccine to the lower respiratory tract of non-human primates elicits optimal immunity and protection

Abstract

Needle-free measles virus vaccination by aerosol inhalation has many potential benefits. The current standard route of vaccination is subcutaneous injection, whereas measles virus is an airborne pathogen. However, the target cells that support replication of live-attenuated measles virus vaccines in the respiratory tract are largely unknown. The aims of this study were to assess the in vivo tropism of live-attenuated measles virus and determine whether respiratory measles virus vaccination should target the upper or lower respiratory tract. Four groups of twelve cynomolgus macaques were immunized with 104 TCID50 of recombinant measles virus vaccine strain Edmonston-Zagreb expressing enhanced green fluorescent protein. The vaccine virus was grown in MRC-5 cells and formulated with identical stabilizers and excipients as used in the commercial MVEZ vaccine produced by the Serum Institute of India. Animals were immunized by hypodermic injection, intra-tracheal inoculation, intra-nasal instillation, or aerosol inhalation. In each group six animals were euthanized at early time points post-vaccination, whereas the other six were followed for 14 months to assess immunogenicity and protection from challenge infection with wild-type measles virus. At early time-points, enhanced green fluorescent protein-positive measles virus-infected cells were detected locally in the muscle, nasal tissues, lungs, and draining lymph nodes. Systemic vaccine virus replication and viremia were virtually absent. Infected macrophages, dendritic cells and tissue-resident lymphocytes predominated. Exclusive delivery of vaccine virus to the lower respiratory tract resulted in highest immunogenicity and protection. This study sheds light on the tropism of a live-attenuated measles virus vaccine and identifies the alveolar spaces as the optimal site for respiratory delivery of measles virus vaccine.

Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens

“…We found no overall change in EBS after MMR vaccination ( fig. S10), which is consistent with observations that the MV vaccine strains are not associated with widespread infection of CD150 + lymphocytes (27,28).…”

Macrophages and Dendritic Cells Are the Predominant Cells Infected in Measles in Humans

“…However, in contrast to the other human cases associated with wild-type MVs, isolated infected columnar epithelial cells were observed in the trachea of the vaccine case together with infected CD3-expressing T cells. However, the observations in this human case mirror those in macaques ( 28 , 29 ). Similar cases of vaccine-induced fatal disease in children with an immune disorder have been published previously ( 38 , 39 ), but to our knowledge there have been no reports of MV receptor status in infected cells in such cases.…”

“…MV infection was not observed in epithelial cells in either the liver or the pancreas. These data suggest that even in vaccine-induced measles, in which the virus can be demonstrated to be capable of using CD46, CD150, and nectin-4 as cellular receptors in vitro ; the in vivo situation in the natural host differs markedly, with the cell types expressing CD150 being those predominantly infected ( 28 , 29 ).…”

Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis

“…The level of protection was nearly complete, even at high challenge doses. We would envision pursuing a similar strategy in humans, similar to respiratory delivery of vaccines for influenza or measles [ 46 – 49 ]. Aerosol delivery would build on the time-honored premise of the oral Sabin vaccine, that vaccination at the site of pathogen entry is superior to parenteral inoculation in the protection conferred.…”