Progress in Respiratory Virus Vaccine Development

ABSTRACT

Viral respiratory infections cause significant morbidity and mortality in infants and young children as well as in at-risk adults and the elderly. Although many viral pathogens are capable of causing respiratory disease, vaccine development has to focus on a limited number of pathogens, such as those that commonly cause serious lower respiratory illness (LRI). Whereas influenza virus vaccines have been available for some time (see the review by Clark and Lynch in this issue), vaccines against other medically important viruses such as respiratory syncytial virus (RSV), the parainfluenza viruses (PIVs), and metapneumovirus (MPVs) are not available. This review aims to provide a brief update on investigational vaccines against RSV, the PIVs, and MPV that have been evaluated in clinical trials or are currently in clinical development.

Vaccine - parainfluenza virus - metapneumovirus - respiratory syncytial virus - clinical trial - clinical development

REFERENCES

• 1 Nair H, Nokes D J, Gessner B D et al.. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.  Lancet. 2010;  375 (9725) 1545-1555
• 2 Mathisen M, Strand T A, Sharma B N et al.. RNA viruses in community-acquired childhood pneumonia in semi-urban Nepal; a cross-sectional study.  BMC Med. 2009;  7 35
• 3 Berkley J A, Munywoki P, Ngama M et al.. Viral etiology of severe pneumonia among Kenyan infants and children.  JAMA. 2010;  303 (20) 2051-2057
• 4 Falsey A R, Hennessey P A, Formica M A, Cox C, Walsh E E. Respiratory syncytial virus infection in elderly and high-risk adults.  N Engl J Med. 2005;  352 (17) 1749-1759
• 5 Black R E, Cousens S, Johnson H L Child Health Epidemiology Reference Group of WHO and UNICEF et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis.  Lancet. 2010;  375 (9730) 1969-1987
• 6 Olsen S J, Thamthitiwat S, Chantra S et al.. Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.  Epidemiol Infect. 2010;  138 (12) 1811-1822
• 7 Falsey A R, Hennessey P A, Formica M A, Cox C, Walsh E E. Respiratory syncytial virus infection in elderly and high-risk adults.  N Engl J Med. 2005;  352 (17) 1749-1759
• 8 Falsey A R, Formica M A, Hennessey P A, Criddle M M, Sullender W M, Walsh E E. Detection of respiratory syncytial virus in adults with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2006;  173 (6) 639-643
• 9 Walsh E E, Peterson D R, Falsey A R. Is clinical recognition of respiratory syncytial virus infection in hospitalized elderly and high-risk adults possible?.  J Infect Dis. 2007;  195 (7) 1046-1051
• 10 Lindsley W G, Blachere F M, Davis K A et al.. Distribution of airborne influenza virus and respiratory syncytial virus in an urgent care medical clinic.  Clin Infect Dis. 2010;  50 (5) 693-698
• 11 Zhang L, Peeples M E, Boucher R C, Collins P L, Pickles R J. Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology.  J Virol. 2002;  76 (11) 5654-5666
• 12 Zhang L, Bukreyev A, Thompson C I et al.. Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium.  J Virol. 2005;  79 (2) 1113-1124
• 13 Schaap-Nutt A, Scull M A, Schmidt A C, Murphy B R, Pickles R J. Growth restriction of an experimental live attenuated human parainfluenza virus type 2 vaccine in human ciliated airway epithelium in vitro parallels attenuation in African green monkeys.  Vaccine. 2010;  28 (15) 2788-2798
• 14 Siezen C L, Bont L, Hodemaekers H M et al.. Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm children is associated with airway remodeling genes and innate immune genes.  Pediatr Infect Dis J. 2009;  28 (4) 333-335
• 15 Bloemers B L, van Furth A M, Weijerman M E et al.. Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis—a prospective birth-cohort study.  Pediatrics. 2007;  120 (4) e1076-e1081
• 16 Bradley J P, Bacharier L B, Bonfiglio J et al.. Severity of respiratory syncytial virus bronchiolitis is affected by cigarette smoke exposure and atopy.  Pediatrics. 2005;  115 (1) e7-e14
• 17 Okiro E A, Ngama M, Bett A, Cane P A, Medley G F, James Nokes D. Factors associated with increased risk of progression to respiratory syncytial virus-associated pneumonia in young Kenyan children.  Trop Med Int Health. 2008;  13 (7) 914-926
• 18 Tristram D A, Hicks Jr W, Hard R. Respiratory syncytial virus and human bronchial epithelium.  Arch Otolaryngol Head Neck Surg. 1998;  124 (7) 777-783
• 19 Johnson J E, Gonzales R A, Olson S J, Wright P F, Graham B S. The histopathology of fatal untreated human respiratory syncytial virus infection.  Mod Pathol. 2007;  20 (1) 108-119
• 20 DeVincenzo J P, Wilkinson T, Vaishnaw A et al.. Viral load drives disease in humans experimentally infected with respiratory syncytial virus.  Am J Respir Crit Care Med. 2010;  182 (10) 1305-1314
• 21 Houben M L, Coenjaerts F E, Rossen J W et al.. Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community.  J Med Virol. 2010;  82 (7) 1266-1271
• 22 Sigurs N, Aljassim F, Kjellman B et al.. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life.  Thorax. 2010;  65 (12) 1045-1052
• 23 Hyvärinen M, Ruotsalainen M, Korppi M. Outcome after bronchiolitis depends on disease definition.  Thorax. 2011;  66 (3) 266-267 author reply 267
• 24 Stein R T, Sherrill D, Morgan W J et al.. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.  Lancet. 1999;  354 (9178) 541-545
• 25 Lukacs N W, Smit J J, Schaller M A, Lindell D M. Regulation of immunity to respiratory syncytial virus by dendritic cells, toll-like receptors, and notch.  Viral Immunol. 2008;  21 (2) 115-122
• 26 El Saleeby C M, Li R, Somes G W, Dahmer M K, Quasney M W, DeVincenzo J P. Surfactant protein A2 polymorphisms and disease severity in a respiratory syncytial virus-infected population.  J Pediatr. 2010;  156 (3) 409-414
• 27 Rämet M, Korppi M, Hallman M. Pattern recognition receptors and genetic risk for rsv infection: value for clinical decision-making?.  Pediatr Pulmonol. 2011;  46 (2) 101-110
• 28 Forton J T, Rowlands K, Rockett K et al.. Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster.  Thorax. 2009;  64 (4) 345-352
• 29 Puthothu B, Bierbaum S, Kopp M V et al.. Association of TNF-alpha with severe respiratory syncytial virus infection and bronchial asthma.  Pediatr Allergy Immunol. 2009;  20 (2) 157-163
• 30 Kulkarni A B, Collins P L, Bacik I et al.. Cytotoxic T cells specific for a single peptide on the M2 protein of respiratory syncytial virus are the sole mediators of resistance induced by immunization with M2 encoded by a recombinant vaccinia virus.  J Virol. 1995;  69 (2) 1261-1264
• 31 Telcian A G, Laza-Stanca V, Edwards M R et al.. RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8 + T cell nonspecific antiviral activity.  J Infect Dis. 2011;  203 (1) 85-94
• 32 Kruijsen D, Bakkers M J, van Uden N O et al.. Serum antibodies critically affect virus-specific CD4 + /CD8 + T cell balance during respiratory syncytial virus infections.  J Immunol. 2010;  185 (11) 6489-6498
• 33 Connors M, Kulkarni A B, Firestone C Y et al.. Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4 + T cells.  J Virol. 1992;  66 (12) 7444-7451
• 34 Connors M, Kulkarni A B, Collins P L et al.. Resistance to respiratory syncytial virus (RSV) challenge induced by infection with a vaccinia virus recombinant expressing the RSV M2 protein (Vac-M2) is mediated by CD8 + T cells, while that induced by Vac-F or Vac-G recombinants is mediated by antibodies.  J Virol. 1992;  66 (2) 1277-1281
• 35 Cautivo K M, Bueno S M, Cortes C M, Wozniak A, Riedel C A, Kalergis A M. Efficient lung recruitment of respiratory syncytial virus-specific Th1 cells induced by recombinant bacillus Calmette-Guérin promotes virus clearance and protects from infection.  J Immunol. 2010;  185 (12) 7633-7645
• 36 Moghaddam A, Olszewska W, Wang B et al.. A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines.  Nat Med. 2006;  12 (8) 905-907
• 37 Welliver T P, Garofalo R P, Hosakote Y et al.. Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses.  J Infect Dis. 2007;  195 (8) 1126-1136
• 38 Reed J L, Welliver T P, Sims G P et al.. Innate immune signals modulate antiviral and polyreactive antibody responses during severe respiratory syncytial virus infection.  J Infect Dis. 2009;  199 (8) 1128-1138
• 39 Eick A, Karron R, Shaw J et al.. The role of neutralizing antibodies in protection of American Indian infants against respiratory syncytial virus disease.  Pediatr Infect Dis J. 2008;  27 (3) 207-212
• 40 Shinoff J J, O'Brien K L, Thumar B et al.. Young infants can develop protective levels of neutralizing antibody after infection with respiratory syncytial virus.  J Infect Dis. 2008;  198 (7) 1007-1015
• 41 Watt P J, Robinson B S, Pringle C R, Tyrrell D A. Determinants of susceptibility to challenge and the antibody response of adult volunteers given experimental respiratory syncytial virus vaccines.  Vaccine. 1990;  8 (3) 231-236
• 42 Plotnicky-Gilquin H, Cyblat-Chanal D, Aubry J P et al.. Gamma interferon-dependent protection of the mouse upper respiratory tract following parenteral immunization with a respiratory syncytial virus G protein fragment.  J Virol. 2002;  76 (20) 10203-10210
• 43 Walsh E E, Falsey A R. Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults.  J Infect Dis. 2004;  190 (2) 373-378
• 44 Smith C B, Purcell R H, Bellanti J A, Chanock R M. Protective effect of antibody to parainfluenza type 1 virus.  N Engl J Med. 1966;  275 (21) 1145-1152
• 45 Malley R, DeVincenzo J, Ramilo O et al.. Reduction of respiratory syncytial virus (RSV) in tracheal aspirates in intubated infants by use of humanized monoclonal antibody to RSV F protein.  J Infect Dis. 1998;  178 (6) 1555-1561
• 46 Lagos R, DeVincenzo J P, Muñoz A et al.. Safety and antiviral activity of motavizumab, a respiratory syncytial virus (RSV)-specific humanized monoclonal antibody, when administered to RSV-infected children.  Pediatr Infect Dis J. 2009;  28 (9) 835-837
• 47 Hall C B, Walsh E E, Long C E, Schnabel K C. Immunity to and frequency of reinfection with respiratory syncytial virus.  J Infect Dis. 1991;  163 (4) 693-698
• 48 Henderson F W, Collier A M, Clyde Jr W A, Denny F W. Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children.  N Engl J Med. 1979;  300 (10) 530-534
• 49 Wright P F, Karron R A, Madhi S A et al.. The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans.  J Infect Dis. 2006;  193 (4) 573-581
• 50 Karron R A, Wright P F, Belshe R B et al.. Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants.  J Infect Dis. 2005;  191 (7) 1093-1104
• 51 Karron R A, Belshe R B, Wright P F et al.. A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in young infants.  Pediatr Infect Dis J. 2003;  22 (5) 394-405
• 52 Williams J V, Weitkamp J H, Blum D L, LaFleur B J, Crowe Jr J E. The human neonatal B cell response to respiratory syncytial virus uses a biased antibody variable gene repertoire that lacks somatic mutations.  Mol Immunol. 2009;  47 (2-3) 407-414
• 53 Crowe Jr J E. Influence of maternal antibodies on neonatal immunization against respiratory viruses.  Clin Infect Dis. 2001;  33 (10) 1720-1727
• 54 Crowe Jr J E, Firestone C Y, Murphy B R. Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines.  J Immunol. 2001;  167 (7) 3910-3918
• 55 Kim H W, Canchola J G, Brandt C D et al.. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine.  Am J Epidemiol. 1969;  89 (4) 422-434
• 56 Wright P F, Karron R A, Belshe R B et al.. The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines.  Vaccine. 2007;  25 (42) 7372-7378
• 57 Collins P L, Chanock R M, Murphy B R. Respiratory syncytial virus. In: Knipe D M, Howley P M, Griffin D E, et al, eds. Fields Virology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 1443-1486
• 58 Piedra P A. Clinical experience with respiratory syncytial virus vaccines.  Pediatr Infect Dis J. 2003;  22 (2, Suppl) S94-S99
• 59 Piedra P A, Cron S G, Jewell A Purified Fusion Protein Vaccine Study Group et al. Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: a multi-center trial in children with cystic fibrosis.  Vaccine. 2003;  21 (19–20) 2448-2460
• 60 Munoz F M, Piedra P A, Glezen W P. Safety and immunogenicity of respiratory syncytial virus purified fusion protein-2 vaccine in pregnant women.  Vaccine. 2003;  21 (24) 3465-3467
• 61 Kneyber M C, Kimpen J L. Advances in respiratory syncytial virus vaccine development.  Curr Opin Investig Drugs. 2004;  5 (2) 163-170
• 62 Bartlett E J, Castaño A, Surman S R, Collins P L, Skiadopoulos M H, Murphy B R. Attenuation and efficacy of human parainfluenza virus type 1 (HPIV1) vaccine candidates containing stabilized mutations in the P/C and L genes.  Virol J. 2007;  4 67
• 63 Nolan S M, Surman S R, Amaro-Carambot E, Collins P L, Murphy B R, Skiadopoulos M H. Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses.  Vaccine. 2005;  23 (39) 4765-4774
• 64 McAuliffe J M, Surman S R, Newman J T et al.. Codon substitution mutations at two positions in the L polymerase protein of human parainfluenza virus type 1 yield viruses with a spectrum of attenuation in vivo and increased phenotypic stability in vitro.  J Virol. 2004;  78 (4) 2029-2036
• 65 Collins P L, Murphy B R. New generation live vaccines against human respiratory syncytial virus designed by reverse genetics.  Proc Am Thorac Soc. 2005;  2 (2) 166-173
• 66 Bukreyev A, Belyakov I M, Berzofsky J A, Murphy B R, Collins P L, Schmidt A C. Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells.  J Virol. 2001;  75 (24) 12128-12140
• 67 Bukreyev A, Lamirande E W, Buchholz U J et al.. Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS.  Lancet. 2004;  363 (9427) 2122-2127
• 68 Bartlett E J, Amaro-Carambot E, Surman S R et al.. Human parainfluenza virus type I (HPIV1) vaccine candidates designed by reverse genetics are attenuated and efficacious in African green monkeys.  Vaccine. 2005;  23 (38) 4631-4646
• 69 Bartlett E J, Amaro-Carambot E, Surman S R, Collins P L, Murphy B R, Skiadopoulos M H. Introducing point and deletion mutations into the P/C gene of human parainfluenza virus type 1 (HPIV1) by reverse genetics generates attenuated and efficacious vaccine candidates.  Vaccine. 2006;  24 (14) 2674-2684
• 70 Bartlett E J, Cruz A M, Esker J et al.. Human parainfluenza virus type 1 C proteins are nonessential proteins that inhibit the host interferon and apoptotic responses and are required for efficient replication in nonhuman primates.  J Virol. 2008;  82 (18) 8965-8977
• 71 Schaap-Nutt A, Higgins C, Amaro-Carambot E et al.. Identification of human parainfluenza virus type 2 (HPIV-2) V protein amino acid residues that reduce binding of V to MDA5 and attenuate HPIV-2 replication in nonhuman primates.  J Virol. 2011;  85 (8) 4007-4019
• 72 Boonyaratanakornkit J, Bartlett E, Schomacker H et al.. The C proteins of human parainfluenza virus type 1 limit double-stranded RNA accumulation that would otherwise trigger MDA5 and protein kinase R.  J Virol. 2011;  85 (4) 1495-1506
• 73 Roldão A, Mellado M C, Castilho L R, Carrondo M J, Alves P M. Virus-like particles in vaccine development.  Expert Rev Vaccines. 2010;  9 (10) 1149-1176
• 74 Jennings G T, Bachmann M F. The coming of age of virus-like particle vaccines.  Biol Chem. 2008;  389 (5) 521-536
• 75 Atkins G J, Fleeton M N, Sheahan B J. Therapeutic and prophylactic applications of alphavirus vectors.  Expert Rev Mol Med. 2008;  10 e33
• 76 Hubby B, Talarico T, Maughan M et al.. Development and preclinical evaluation of an alphavirus replicon vaccine for influenza.  Vaccine. 2007;  25 (48) 8180-8189
• 77 Kamrud K I, Custer M, Dudek J M et al.. Alphavirus replicon approach to promoterless analysis of IRES elements.  Virology. 2007;  360 (2) 376-387
• 78 Thompson J M, Nicholson M G, Whitmore A C et al.. Nonmucosal alphavirus vaccination stimulates a mucosal inductive environment in the peripheral draining lymph node.  J Immunol. 2008;  181 (1) 574-585
• 79 Tonkin D R, Jorquera P, Todd T, Beard C W, Johnston R E, Barro M. Alphavirus replicon-based enhancement of mucosal and systemic immunity is linked to the innate response generated by primary immunization.  Vaccine. 2010;  28 (18) 3238-3246
• 80 Mok H, Lee S, Utley T J et al.. Venezuelan equine encephalitis virus replicon particles encoding respiratory syncytial virus surface glycoproteins induce protective mucosal responses in mice and cotton rats.  J Virol. 2007;  81 (24) 13710-13722
• 81 Bernstein D I, Reap E A, Katen K et al.. Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers.  Vaccine. 2009;  28 (2) 484-493
• 82 Peiperl L, Morgan C, Moodie Z NIAID HIV Vaccine Trials Network et al. Safety and immunogenicity of a replication-defective adenovirus type 5 HIV vaccine in Ad5-seronegative persons: a randomized clinical trial (HVTN 054).  PLoS ONE. 2010;  5 (10) e13579
• 83 Jaoko W, Karita E, Kayitenkore K et al.. Safety and immunogenicity study of Multiclade HIV-1 adenoviral vector vaccine alone or as boost following a multiclade HIV-1 DNA vaccine in Africa.  PLoS ONE. 2010;  5 (9) e12873
• 84 Song K, Bolton D L, Wei C J et al.. Genetic immunization in the lung induces potent local and systemic immune responses.  Proc Natl Acad Sci U S A. 2010;  107 (51) 22213-22218
• 85 Dudareva M, Andrews L, Gilbert S C et al.. Prevalence of serum neutralizing antibodies against chimpanzee adenovirus 63 and human adenovirus 5 in Kenyan children, in the context of vaccine vector efficacy.  Vaccine. 2009;  27 (27) 3501-3504
• 86 Ersching J, Hernandez M I, Cezarotto F S et al.. Neutralizing antibodies to human and simian adenoviruses in humans and New-World monkeys.  Virology. 2010;  407 (1) 1-6
• 87 Buchbinder S P, Mehrotra D V, Duerr A Step Study Protocol Team et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.  Lancet. 2008;  372 (9653) 1881-1893
• 88 Graham B S. Biological challenges and technological opportunities for respiratory syncytial virus vaccine development.  Immunol Rev. 2011;  239 (1) 149-166
• 89 Graham B. Gene-based vector vaccines for respiratory syncytial virus. Paper presented at: 7th International RSV Symposium; December 4, 2010; Rotterdam, The Netherlands
• 90 Langley J M, Sales V, McGeer A et al.. A dose-ranging study of a subunit respiratory syncytial virus subtype A vaccine with and without aluminum phosphate adjuvantation in adults >or =65 years of age.  Vaccine. 2009;  27 (42) 5913-5919
• 91 Falsey A R, Walsh E E, Capellan J et al.. Comparison of the safety and immunogenicity of 2 respiratory syncytial virus (rsv) vaccines—nonadjuvanted vaccine or vaccine adjuvanted with alum—given concomitantly with influenza vaccine to high-risk elderly individuals.  J Infect Dis. 2008;  198 (9) 1317-1326
• 92 Wright P F, Karron R A, Belshe R B et al.. Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy.  J Infect Dis. 2000;  182 (5) 1331-1342
• 93 Collins P L, Hill M G, Camargo E, Grosfeld H, Chanock R M, Murphy B R. Production of infectious human respiratory syncytial virus from cloned cDNA confirms an essential role for the transcription elongation factor from the 5′ proximal open reading frame of the M2 mRNA in gene expression and provides a capability for vaccine development.  Proc Natl Acad Sci U S A. 1995;  92 (25) 11563-11567
• 94 Jin H, Zhou H, Cheng X, Tang R, Munoz M, Nguyen N. Recombinant respiratory syncytial viruses with deletions in the NS1, NS2, SH, and M2-2 genes are attenuated in vitro and in vivo.  Virology. 2000;  273 (1) 210-218
• 95 Teng M N, Whitehead S S, Bermingham A et al.. Recombinant respiratory syncytial virus that does not express the NS1 or M2-2 protein is highly attenuated and immunogenic in chimpanzees.  J Virol. 2000;  74 (19) 9317-9321
• 96 McGinnes L W, Gravel K A, Finberg R W et al.. Assembly and immunological properties of Newcastle disease virus-like particles containing the respiratory syncytial virus F and G proteins.  J Virol. 2011;  85 (1) 366-377
• 97 Murawski M R, McGinnes L W, Finberg R W et al.. Newcastle disease virus-like particles containing respiratory syncytial virus G protein induced protection in BALB/c mice, with no evidence of immunopathology.  J Virol. 2010;  84 (2) 1110-1123
• 98 Pantua H D, McGinnes L W, Peeples M E, Morrison T G. Requirements for the assembly and release of Newcastle disease virus-like particles.  J Virol. 2006;  80 (22) 11062-11073
• 99 Skiadopoulos M H, Surman S, Tatem J M et al.. Identification of mutations contributing to the temperature-sensitive, cold-adapted, and attenuation phenotypes of the live-attenuated cold-passage 45 (cp45) human parainfluenza virus 3 candidate vaccine.  J Virol. 1999;  73 (2) 1374-1381
• 100 Belshe R B, Newman F K, Tsai T F et al.. Phase 2 evaluation of parainfluenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6-18 months old.  J Infect Dis. 2004;  189 (3) 462-470
• 101 Belshe R B, Newman F K, Anderson E L et al.. Evaluation of combined live, attenuated respiratory syncytial virus and parainfluenza 3 virus vaccines in infants and young children.  J Infect Dis. 2004;  190 (12) 2096-2103
• 102 Bernstein D, Charenkavanich S, Falloon J. Safety profile, immunogenicity, and viral shedding of rHPIV3cp45, a live, attenuated human parainfluenzavirus type 3 (PIV3) vaccine. Paper presented at: 7th International RSV Symposium; December 4, 2010; Rotterdam, The Netherlands
• 103 van Wyke Coelingh K L, Winter C C, Tierney E L, London W T, Murphy B R. Attenuation of bovine parainfluenza virus type 3 in nonhuman primates and its ability to confer immunity to human parainfluenza virus type 3 challenge.  J Infect Dis. 1988;  157 (4) 655-662
• 104 Karron R A, Makhene M, Gay K, Wilson M H, Clements M L, Murphy B R. Evaluation of a live attenuated bovine parainfluenza type 3 vaccine in two- to six-month-old infants.  Pediatr Infect Dis J. 1996;  15 (8) 650-654
• 105 Greenberg D P, Walker R E, Lee M S et al.. A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy.  J Infect Dis. 2005;  191 (7) 1116-1122
• 106 Schmidt A C, McAuliffe J M, Huang A et al.. Bovine parainfluenza virus type 3 (BPIV3) fusion and hemagglutinin-neuraminidase glycoproteins make an important contribution to the restricted replication of BPIV3 in primates.  J Virol. 2000;  74 (19) 8922-8929
• 107 Tang R S, MacPhail M, Schickli J H et al.. Parainfluenza virus type 3 expressing the native or soluble fusion (F) protein of respiratory syncytial virus (RSV) confers protection from RSV infection in African green monkeys.  J Virol. 2004;  78 (20) 11198-11207
• 108 Tang R S, Spaete R R, Thompson M W et al.. Development of a PIV-vectored RSV vaccine: preclinical evaluation of safety, toxicity, and enhanced disease and initial clinical testing in healthy adults.  Vaccine. 2008;  26 (50) 6373-6382
• 109 Schmidt A C, McAuliffe J M, Murphy B R, Collins P L. Recombinant bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the respiratory syncytial virus (RSV) G and F proteins can be used to achieve simultaneous mucosal immunization against RSV and HPIV3.  J Virol. 2001;  75 (10) 4594-4603
• 110 Schmidt A C, Wenzke D R, McAuliffe J M et al.. Mucosal immunization of rhesus monkeys against respiratory syncytial virus subgroups A and B and human parainfluenza virus type 3 by using a live cDNA-derived vaccine based on a host range-attenuated bovine parainfluenza virus type 3 vector backbone.  J Virol. 2002;  76 (3) 1089-1099
• 111 Gomez M, Mufson M A, Dubovsky F, Knightly C, Zeng W, Losonsky G. Phase-I study MEDI-534, of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza-3 virus in seropositive children.  Pediatr Infect Dis J. 2009;  28 (7) 655-658
• 112 Bernstein D, Malkin E, Charenkavanich S, Dubovsky F. Safety profile, immunogenicity, and viral shedding of MEDI-534, a live, attenuated respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) vaccine in RSV/PIV3 seronegative children. Paper presented at: 7th International RSV Symposium; December 4, 2010; Rotterdam, The Netherlands
• 113 Biacchesi S, Pham Q N, Skiadopoulos M H, Murphy B R, Collins P L, Buchholz U J. Infection of nonhuman primates with recombinant human metapneumovirus lacking the SH, G, or M2-2 protein categorizes each as a nonessential accessory protein and identifies vaccine candidates.  J Virol. 2005;  79 (19) 12608-12613
• 114 Buchholz U J, Nagashima K, Murphy B R, Collins P L. Live vaccines for human metapneumovirus designed by reverse genetics.  Expert Rev Vaccines. 2006;  5 (5) 695-706
• 115 Pham Q N, Biacchesi S, Skiadopoulos M H, Murphy B R, Collins P L, Buchholz U J. Chimeric recombinant human metapneumoviruses with the nucleoprotein or phosphoprotein open reading frame replaced by that of avian metapneumovirus exhibit improved growth in vitro and attenuation in vivo.  J Virol. 2005;  79 (24) 15114-15122
• 116 Newman J T, Riggs J M, Surman S R et al.. Generation of recombinant human parainfluenza virus type 1 vaccine candidates by importation of temperature-sensitive and attenuating mutations from heterologous paramyxoviruses.  J Virol. 2004;  78 (4) 2017-2028
• 117 Van Cleve W, Amaro-Carambot E, Surman S R et al.. Attenuating mutations in the P/C gene of human parainfluenza virus type 1 (HPIV1) vaccine candidates abrogate the inhibition of both induction and signaling of type I interferon (IFN) by wild-type HPIV1.  Virology. 2006;  352 (1) 61-73
• 118 Boonyaratanakornkit J B, Bartlett E J, Amaro-Carambot E, Collins P L, Murphy B R, Schmidt A C. The C proteins of human parainfluenza virus type 1 (HPIV1) control the transcription of a broad array of cellular genes that would otherwise respond to HPIV1 infection.  J Virol. 2009;  83 (4) 1892-1910
• 119 Nolan S M, Surman S R, Amaro-Carambot E, Collins P L, Murphy B R, Skiadopoulos M H. Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses.  Vaccine. 2005;  23 (39) 4765-4774
• 120 Nolan S M, Skiadopoulos M H, Bradley K et al.. Recombinant human parainfluenza virus type 2 vaccine candidates containing a 3′ genomic promoter mutation and L polymerase mutations are attenuated and protective in non-human primates.  Vaccine. 2007;  25 (34) 6409-6422