Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant.
Respiratory syncytial virus (RSV) infection of children previously immunized with a nonlive, formalin-inactivated (FI)-RSV vaccine has been associated with serious enhanced respiratory disease (ERD). Consequently, detailed studies of potential ERD are a critical step in the development of nonlive RSV vaccines targeting RSV-naive children and infants. The fusion glycoprotein (F) of RSV in either its postfusion (post-F) or prefusion (pre-F) conformation is a target for neutralizing antibodies and therefore an attractive antigen candidate for a pediatric RSV subunit vaccine. Here, we report the evaluation of RSV post-F and pre-F in combination with glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE) and alum adjuvants in the cotton rat model. Immunization with optimal doses of RSV F antigens in the presence of GLA-SE induced high titers of virus-neutralizing antibodies and conferred complete lung protection from virus challenge, with no ERD signs in the form of alveolitis. To mimic a waning immune response, and to assess priming for ERD under suboptimal conditions, an antigen dose de-escalation study was performed in the presence of either GLA-SE or alum. At low RSV F doses, alveolitis-associated histopathology was unexpectedly observed with either adjuvant at levels comparable to FI-RSV-immunized controls. This occurred despite neutralizing-antibody titers above the minimum levels required for protection and with no/low virus replication in the lungs. These results emphasize the need to investigate a pediatric RSV vaccine candidate carefully for priming of ERD over a wide dose range, even in the presence of strong neutralizing activity, Th1 bias-inducing adjuvant, and protection from virus replication in the lower respiratory tract.IMPORTANCERSV disease is of great importance worldwide, with the highest burden of serious disease occurring upon primary infection in infants and children. FI-RSV-induced enhanced disease, observed in the 1960s, presented a major and ongoing obstacle for the development of nonlive RSV vaccine candidates. The findings presented here underscore the need to evaluate a nonlive RSV vaccine candidate during preclinical development over a wide dose range in the cotton rat RSV enhanced-disease model, as suboptimal dosing of several RSV F subunit vaccine candidates led to the priming for ERD. These observations are relevant to the validity of the cotton rat model itself and to safe development of nonlive RSV vaccines for seronegative infants and children.
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA.
Kirsten
K
Schneider-Ohrum
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA cayattec@medimmune.com.
Corinne
C
Cayatte
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA.
Angie Snell
AS
Bennett
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA.
Gaurav Manohar
GM
Rajani
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA.
Patrick
P
McTamney
Department of Laboratory Animal Resources, Medimmune, Gaithersburg, Maryland, USA.
Krystal
K
Nacel
Department of Laboratory Animal Resources, Medimmune, Gaithersburg, Maryland, USA.
Leigh
L
Hostetler
Pathology Department, Medimmune, Gaithersburg, Maryland, USA.
Lily
L
Cheng
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA.
Kuishu
K
Ren
Department of Statistical Sciences, Medimmune, Gaithersburg, Maryland, USA.
Terrence
T
O'Day
Independent Researcher, Potomac, Maryland, USA.
Gregory A
GA
Prince
Department of Infectious Disease/Vaccines, Medimmune, Gaithersburg, Maryland, USA.
Michael P
MP
McCarthy
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D019067:Antibody-Dependent Enhancement; D004195:Disease Models, Animal; D008050:Lipid A / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000517:prevention & control; D022261:Respiratory Syncytial Virus Vaccines / Q000235:genetics / Q000276:immunology*; D016205:Sigmodontinae; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C526850:F protein, human respiratory syncytial virus; D008050:Lipid A; D011994:Recombinant Proteins; D022261:Respiratory Syncytial Virus Vaccines; D014614:Vaccines, Synthetic; D014760:Viral Fusion Proteins; C041524:aluminum sulfate
GLA-SE; RSV; RSV F; cotton rat; enhanced RSV disease; respiratory syncytial virus; vaccine