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• Intranasal Mnull RSV vaccine moderately improved most endpoints after RSV infection. • Intrapulmonary Mnull RSV vaccination induced RSV NA responses lasting >4–6 months. • Intrapulmonary Mnull RSV vaccination markedly reduced tachypnea after RSV infection. • Intrapulmonary Mnull RSV vaccination prevented viral replication after RSV infection. • Intrapulmonary Mnull RSV vaccination reduced work of breathing after RSV infection. Respiratory syncytial virus (RSV) is the major viral respiratory pathogen for human infants and children. Despite a severe global burden incurred by annual RSV epidemics, there is no licensed RSV vaccine. We have developed an RSV vaccine from a human RSV strain from which the gene for the viral M protein has been deleted ("Mnull RSV"). RSV infects airway cells and produces each of its proteins. The M protein is responsible for reassembling the various other synthesized viral proteins into new, intact virus. In the absence of the M protein, therefore, reassembly does not occur, and the Mnull RSV does not replicate. We vaccinated 2-week old infant baboons with Mnull RSV either intranasally (IN) or directly into the lung (intratracheal, or IT), then infected these animals by inoculating human RSV directly into the lung. IN vaccination induced inconsistent serum RSV neutralizing antibody (NA) responses, but provided moderate reductions in respiratory rates, overall signs of illness and viral replication in bronchoalveolar lavage (BAL) fluid following infection. Intratracheal vaccination induced much stronger RSV NA responses, which persisted for at least 4–6 months. Following RSV infection, animals vaccinated by the IT route had much greater reductions in tachypnea and work of breathing than animals vaccinated IN, and had undetectable amounts of virus in BAL fluids. These results support the further development of IT Mnull RSV vaccination to reduce the impact of RSV infection in humans. [ABSTRACT FROM AUTHOR]