Evaluation of a Live, Cold‐Passaged, Temperature‐Sensitive, Respiratory Syncytial Virus Vaccine Candidate in Infancy

Wright, Peter F.; Karron, Ruth A.; Belshe, Robert B.; Thompson, Juliette; Crowe, James E.; Boyce, Thomas G.; Halburnt, Lisa L.; Reed, George W.; Whitehead, Stephen S.; Anderson, Edwin L.; Wittek, Alec E.; Casey, Roberta; Eichelberger, Maryna C.; Thumar, Bhagvanji; Randolph, Valerie B.; Udem, Stephen A.; Chanock, Robert M.; Murphy, Brian R.

doi:10.1086/315859

Cited by 285 publications

(209 citation statements)

References 47 publications

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“…In humans, administration of a live attenuated RSV vaccine to 1-moold infants possessing maternally acquired RSV Abs induced a high level of resistance to replication of a second dose of vaccine virus given 1 mo later (50). Similar to the data presented here, very few of those infants exhibited a serum RSV-specific IgG or neutralizing Ab response following immunization in the presence of RSV-specific maternal Abs.…”

Section: Discussionsupporting

confidence: 80%

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

Crowe

Firestone

Murphy

2001

The Journal of Immunology

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A respiratory syncytial virus (RSV) vaccine will need to be administered by 1 mo of age to protect young infants; therefore, it will need to be effective in the presence of maternally acquired RSV Abs. In the present study, the immunogenicity and efficacy of two live attenuated RSV vaccine candidates of different level of attenuation were evaluated in mice passively immunized with varying quantities of RSV Abs. The replication of the RSV vaccines was suppressed in the lower, but not the upper, respiratory tract of the passively immunized mice. Immunization with either vaccine candidate was highly efficacious against challenge with wild-type RSV in both passively immunized and control mice. Nonetheless, a high level of immunity was seen even in passively/actively immunized animals that failed to develop a humoral immune response, suggesting that T cells mediated the immunity. Depletion of CD4+ and CD8+ T cells in passively/actively immunized and control animals at the time of challenge with wild-type RSV demonstrated that CD4+ and CD8+ T cells made significant independent contributions to the restriction of replication of RSV challenge virus in both the upper and lower respiratory tracts. Although passively acquired serum RSV Abs suppressed the primary systemic and mucosal Ab responses of IgM, IgG, and IgA isotypes, B lymphocytes were nevertheless primed for robust secondary Ab responses. Thus, immunity mediated by CD4+ and CD8+ T cells and Abs can be readily induced in mice by live RSV vaccine candidates in the presence of physiologic levels of RSV neutralizing Abs.

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Section: Discussionsupporting

confidence: 80%

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

Crowe

Firestone

Murphy

2001

The Journal of Immunology

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“…A second factor is the immunosuppressive effect of maternally derived serum antibodies, with the greatest impact in the first few months of life (12). In addition, evaluation of pediatric vaccines is multistep for safety reasons, and involves progression from adults to seropositive children to seronegative children to RSV-naive infants of 1 to 2 months of age, approximating the target population (13,14).…”

Section: Rsv Vaccinesmentioning

confidence: 99%

“…A number of live-attenuated RSV vaccine candidates were developed over several decades by conventional methods (13,17,18). The most promising set of candidates was developed by serial passage at increasingly suboptimal temperature (cold passage [cp]) followed by chemical mutagenesis and screening to identify temperature-sensitive (ts) mutants.…”

Section: Rsv Vaccinesmentioning

confidence: 99%

“…The most promising set of candidates was developed by serial passage at increasingly suboptimal temperature (cold passage [cp]) followed by chemical mutagenesis and screening to identify temperature-sensitive (ts) mutants. Preclinical and clinical analysis of a cpRSV derivative and a number of further cptsRSV derivatives showed that they were attenuated but retained an unacceptable level of residual virulence (13,18). The most extensively characterized candidate, called cpts248/404, caused nasal congestion when evaluated in 1-to 2-month-old infants (13).…”

Section: Rsv Vaccinesmentioning

confidence: 99%

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New Generation Live Vaccines against Human Respiratory Syncytial Virus Designed by Reverse Genetics

Collins

Murphy²

2005

Proceedings of the American Thoracic Society

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Development of a live pediatric vaccine against human respiratory syncytial virus (RSV) is complicated by the need to immunize young infants and the difficulty in balancing attenuation and immunogenicity. The ability to introduce desired mutations into infectious virus by reverse genetics provides a method for identifying and designing highly defined attenuating mutations. These can be introduced in combinations as desired to achieve gradations of attenuation. Attenuation is based on several strategies: multiple independent temperature-sensitive point mutations in the polymerase, a temperature-sensitive point mutation in a transcription signal, a set of non-temperature-sensitive mutations involving several genes, deletion of a viral RNA synthesis regulatory protein, and deletion of viral IFN ␣/␤ antagonists. The genetic stability of the live vaccine can be increased by judicious choice of mutations. The virus also can be engineered to increase the level of expression of the protective antigens. Protective antigens from antigenically distinct RSV strains can be added or swapped to increase the breadth of coverage. Alternatively, the major RSV protective antigens can be expressed from transcription units added to an attenuated parainfluenza vaccine virus, making a bivalent vaccine. This would obviate the difficulties inherent in the fragility and inefficient in vitro growth of RSV, simplifying vaccine design and use.

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“…They represent a significant challenge for the development of novel vaccines against infant pathogens for which protection requires the induction of high titer Ab responses already in the first month of life. As an example, a novel live attenuated respiratory syncytial virus vaccine demonstrated to be strongly immunogenic at 3-5 mo of age failed to induce neutralizing serum IgG responses in 1-to 2-mo-old infants, the target group for prevention of severe respiratory syncytial virus disease (5).…”

Section: T He Level Of Igg Ab Responses To T-dependent Ags That Canmentioning

confidence: 99%

Unresponsiveness to Lymphoid-Mediated Signals at the Neonatal Follicular Dendritic Cell Precursor Level Contributes to Delayed Germinal Center Induction and Limitations of Neonatal Antibody Responses to T-Dependent Antigens

Pihlgren

Tougne

Bozzotti

et al. 2003

The Journal of Immunology

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The factors limiting neonatal and infant IgG Ab responses to T-dependent Ags are only partly known. In this study, we assess how these B cell responses are influenced by the postnatal development of the spleen and lymph node microarchitecture. When BALB/c mice were immunized with alum-adsorbed tetanus toxoid at various stages of their immune development, a major functional maturation step for induction of serum IgG, Ab-secreting cells, and germinal center (GC) responses was identified between the second and the third week of life. This correlated with the development of the follicular dendritic cell (FDC) network, as mature FDC clusters only appeared at 2 wk of age. Adoptive transfer of neonatal splenocytes into adult SCID mice rapidly induced B cell follicles and FDC precursor differentiation into mature FDC, indicating effective recruitment and signaling capacity of neonatal B cells. In contrast, adoptive transfer of adult splenocytes into neonatal SCID mice induced primary B cell follicles without any differentiation of mature FDC and failed to correct limitations of tetanus toxoid-induced GC. Thus, unresponsiveness to lymphoid-mediated signals at the level of neonatal FDC precursors delays FDC maturation and GC induction, thus limiting primary Ab-secreting cell responses to T-dependent Ags in early postnatal life.

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Evaluation of a Live, Cold‐Passaged, Temperature‐Sensitive, Respiratory Syncytial Virus Vaccine Candidate in Infancy

Cited by 285 publications

References 47 publications

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

New Generation Live Vaccines against Human Respiratory Syncytial Virus Designed by Reverse Genetics

Unresponsiveness to Lymphoid-Mediated Signals at the Neonatal Follicular Dendritic Cell Precursor Level Contributes to Delayed Germinal Center Induction and Limitations of Neonatal Antibody Responses to T-Dependent Antigens

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