Implication of respiratory syncytial virus (RSV) F transgene sequence heterogeneity observed in Phase 1 evaluation of MEDI-534, a live attenuated parainfluenza type 3 vectored RSV vaccine

Yang, Chin-Fen; Wang, C. Kathy; Malkin, Elissa; Schickli, Jeanne H.; Shambaugh, Cindy; Zuo, Fengrong; Galinski, Mark S.; Dubovsky, Filip; Tang, Roderick S.

doi:10.1016/j.vaccine.2013.04.006

Cited by 43 publications

(43 citation statements)

References 12 publications

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“…were reminiscent of ones described previously in the rB/ HPIV3-F2 virus from the nasal washes of vaccinated children (20). The other three mutant clones had mutations in the N and/or L protein whose effects are unknown.…”

Section: ⌬170mentioning

confidence: 52%

“…Previous clinical evaluation of the rB/HPIV3-F2 construct showed that the stability of RSV F expression is an important consideration (20). In that study, ϳ2.5% of the virus in the clinical trial material used for human administration did not express RSV F, and approximately half of the nasal wash specimens from vaccine recipients contained virus with mutations expected to reduce or ablate expression of the RSV F insert (20).…”

Section: ⌬170mentioning

confidence: 92%

“…In that study, ϳ2.5% of the virus in the clinical trial material used for human administration did not express RSV F, and approximately half of the nasal wash specimens from vaccine recipients contained virus with mutations expected to reduce or ablate expression of the RSV F insert (20). This suggests that in vitro and in vivo there was selection of variants in which expression of the RSV F insert had been silenced.…”

Section: ⌬170mentioning

confidence: 95%

“…Clinical evaluation of an rB/HPIV3-RSV-F construct in seronegative children showed that it was infectious, well tolerated, and attenuated but was less immunogenic against RSV F than hoped (7). This appeared to be due at least in part to genetic instability that silenced expression of the RSV F insert in a substantial proportion of vector particles (20). However, further studies are under way to stabilize the RSV F insert and enhance immunogenicity (21).…”

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confidence: 99%

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Attenuated Human Parainfluenza Virus Type 1 (HPIV1) Expressing the Fusion Glycoprotein of Human Respiratory Syncytial Virus (RSV) as a Bivalent HPIV1/RSV Vaccine

Mackow

Amaro-Carambot

Liang

et al. 2015

J Virol

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Live attenuated recombinant human parainfluenza virus type 1 (rHPIV1) was investigated as a vector to express the respiratory syncytial virus (RSV) fusion (F) glycoprotein, to provide a bivalent vaccine against RSV and HPIV1. The RSV F gene was engineered to include HPIV1 transcription signals and inserted individually into three gene locations in each of the two attenuated rHPIV1 backbones. Each backbone contained a single previously described attenuating mutation that was stabilized against deattenuation, specifically, a non-temperature-sensitive deletion mutation involving 6 nucleotides in the overlapping P/C open reading frames (ORFs) (C ⌬170 ) or a temperature-sensitive missense mutation in the L ORF (L Y942A ). The insertion sites in the genome were pre-N (F1), N-P (F2), or P-M (F3) and were identical for both backbones. In vitro, the presence of the F insert reduced the rate of virus replication, but the final titers were the same as the final titer of wild-type (wt) HPIV1. High levels of RSV F expression in cultured cells were observed with rHPIV1-C ⌬170 -F1, -F2, and -F3 and rHPIV1-L Y942A -F1. In hamsters, the rHPIV1-C ⌬170 -F1, -F2, and -F3 vectors were moderately restricted in the nasal turbinates, highly restricted in lungs, and genetically stable in vivo. Among the C ⌬170 vectors, the F1 virus was the most immunogenic and protective against wt RSV challenge. The rHPIV1-L Y942A vectors were highly restricted in vivo and were not detectably immunogenic or protective, indicative of overattenuation. The C ⌬170 -F1 construct appears to be suitably attenuated and immunogenic for further development as a bivalent intranasal pediatric vaccine. H uman respiratory syncytial virus (RSV) is the leading viral cause of severe acute respiratory infection (ARI) in infants and young children worldwide. RSV is an enveloped, nonsegmented, negative-strand RNA virus of the family Paramyxoviridae. RSV infects early in life and is responsible globally for an estimated 34 million annual pediatric cases of acute bronchiolitis and pneumonia, 4 million hospitalizations, and up to 199,000 pediatric deaths, 99% of which occur in the developing world (1). The human parainfluenza viruses (HPIVs) are also enveloped nonsegmented negative-strand RNA viruses of the family Paramyxoviridae. HPIV serotype 1 (HPIV1), HPIV2, and HPIV3 in particular are important agents of pediatric ARI and in aggregate are second in importance only to RSV (2). No vaccines are currently available for RSV or any of the HPIVs. Here we describe the development and evaluation of attenuated strains of HPIV1 as vectors to express the fusion (F) protein of RSV as a bivalent HPIV1/RSV vaccine.A formalin-inactivated RSV vaccine evaluated in infants and children in the 1960s was poorly protective and, paradoxically, primed for greatly enhanced RSV disease (3, 4). Markers for RSV disease enhancement have also been observed with purified RSV subunit vaccines in experimental animals (5, 6). Therefore, inactivated and subunit vaccines are considered contraindic...

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Section: ⌬170mentioning

confidence: 52%

Section: ⌬170mentioning

confidence: 92%

Section: ⌬170mentioning

confidence: 95%

mentioning

confidence: 99%

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Attenuated Human Parainfluenza Virus Type 1 (HPIV1) Expressing the Fusion Glycoprotein of Human Respiratory Syncytial Virus (RSV) as a Bivalent HPIV1/RSV Vaccine

Mackow

Amaro-Carambot

Liang

et al. 2015

J Virol

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“…If this attenuation was due, at least in part, to expression of the GP insert, then mutations that silence expression of GP could provide a selective advantage. This is reminiscent of observations with a PIV vector expressing the RSV F protein, which also acquired mutations that would silence expression of the foreign gene (26). However, if silencing the expression of EBOV GP did provide a selective advantage, that advantage may not be very great, because there was not a progressive increase with time in the loss of GP expression during AGM infection.…”

Section: Discussionmentioning

confidence: 92%

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Lingemann

Liu

Surman

et al. 2017

J Virol

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The recent 2014-2016 Ebola virus (EBOV) outbreak prompted increased efforts to develop vaccines against EBOV disease. We describe the development and preclinical evaluation of an attenuated recombinant human parainfluenza virus type 1 (rHPIV1) expressing the membrane-anchored form of EBOV glycoprotein GP, as an intranasal (i.n.) EBOV vaccine. GP was codon optimized and expressed either as a full-length protein or as an engineered chimeric form in which its transmembrane and cytoplasmic tail (TMCT) domains were replaced with those of the HPIV1 F protein in an effort to enhance packaging into the vector particle and immunogenicity. GP was inserted either preceding the N gene (pre-N) or between the N and P genes (N-P) of rHPIV1 bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ). The constructs grew to high titers and efficiently and stably expressed GP. Viruses were attenuated, replicating at low titers over several days, in the respiratory tract of African green monkeys (AGMs). Two doses of candidates expressing GP from the pre-N position elicited higher GP neutralizing serum antibody titers than the N-P viruses, and unmodified GP induced higher levels than its TMCT counterpart. Unmodified EBOV GP was packaged into the HPIV1 particle, and the TMCT modification did not increase packaging or immunogenicity but rather reduced the stability of GP expression during in vivo replication. In conclusion, we identified an attenuated and immunogenic i.n. vaccine candidate expressing GP from the pre-N position. It is expected to be well tolerated in humans and is available for clinical evaluation.IMPORTANCE EBOV hemorrhagic fever is one of the most lethal viral infections and lacks a licensed vaccine. Contact of fluids from infected individuals, including droplets or aerosols, with mucosal surfaces is an important route of EBOV spread during a natural outbreak, and aerosols also might be exploited for intentional virus spread. Therefore, vaccines that protect against mucosal as well as systemic inoculation are needed. We evaluated a version of human parainfluenza virus type 1 (HPIV1) bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ) as an intranasal vaccine vector to express the EBOV glycoprotein GP. We evaluated expression from two different genome positions (pre-N and N-P) and investigated the use of vector packaging signals. African green monkeys immunized with two doses of the vector expressing GP from the pre-N position developed high titers of GP neutralizing serum antibodies. The attenuated vaccine candidate is expected to be safe and immunogenic and is available for clinical development.

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Negative-Strand RNA Virus-Vectored Vaccines

Murr,

Mettenleiter

2024

Methods in Molecular Biology

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Implication of respiratory syncytial virus (RSV) F transgene sequence heterogeneity observed in Phase 1 evaluation of MEDI-534, a live attenuated parainfluenza type 3 vectored RSV vaccine

Cited by 43 publications

References 12 publications

Attenuated Human Parainfluenza Virus Type 1 (HPIV1) Expressing the Fusion Glycoprotein of Human Respiratory Syncytial Virus (RSV) as a Bivalent HPIV1/RSV Vaccine

Attenuated Human Parainfluenza Virus Type 1 (HPIV1) Expressing the Fusion Glycoprotein of Human Respiratory Syncytial Virus (RSV) as a Bivalent HPIV1/RSV Vaccine

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Negative-Strand RNA Virus-Vectored Vaccines

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