Pathogens usually exist in heterogeneous variants, like subtypes and strains. Quantifying treatment effects on the different variants is important for guiding prevention policies and vaccine development. Here, we ground analyses of variant-specific effects on a formal framework for causal inference. This allows us to clarify the interpretation of existing methods and define new estimands. Unlike most of the existing literature, we explicitly consider the (realistic) setting with interference in the target population: even if individuals can be sensibly perceived as iid in randomized trial data, there will often be interference in the target population where treatments, such as vaccines, are rolled out. Thus, one of our contributions is to derive explicit conditions guaranteeing that commonly reported vaccine efficacy parameters quantify well-defined causal effects, also in the presence of interference. Furthermore, our results give alternative justifications for reporting estimands on the relative, rather than absolute, scale. We illustrate the findings with an analysis of a large HIV1 vaccine trial, where there is interest in distinguishing vaccine effects on viruses with different genome sequences.

2023-04-01·Molecular therapy : the journal of the American Society of Gene Therapy

Evaluation of repRNA vaccine for induction and in utero transfer of maternal antibodies in a pregnant rabbit model

Article

作者: Warner, Nikole L. ; Staats, Herman F. ; Sather, D. Noah ; Erasmus, Jesse H. ; Landon, Chelsea D. ; Archer, Jacob ; Randall, Samantha ; Berube, Bryan J. ; Krieger, Kyle ; Khandhar, Amit P.

Mother-to-child transmission is a major route for infections in newborns. Vaccination in mothers to leverage the maternal immune system is a promising approach to vertically transfer protective immunity. During infectious disease outbreaks, such as the 2016 Zika virus (ZIKV) outbreak, rapid availability of vaccines can prove critical in reducing widespread disease burden. The recent successes of mRNA vaccines support their evaluation in pregnant animal models to justify their use in neonatal settings. Here we evaluated immunogenicity of self-amplifying replicon (repRNA) vaccines, delivered with our clinical-stage LION nanoparticle formulation, in pregnant rabbits using ZIKV and HIV-1 as model disease targets. We showed that LION/repRNA vaccines induced robust antigen-specific antibody responses in adult pregnant rabbits that passively transferred to newborn kits in utero. Using a matrixed study design, we further elucidate the effect of vaccination in kits on the presence of pre-existing maternal antibodies. Our findings showed that timing of maternal vaccination is critical in maximizing in utero antibody transfer, and subsequent vaccination in newborns maintained elevated antibody levels compared with no vaccination. Overall, our results support further development of the LION/repRNA vaccine platform for maternal and neonatal settings.

2022-07-01·Genes & Genomics

Analysis of evolutionary and genetic patterns in structural genes of primate lentiviruses

Article

作者: Son, Hyeon S ; Min, Xianglan ; Cho, Myeongji

BACKGROUND:

Primate lentiviruses (HIV1, HIV2, and Simian immunodeficiency virus [SIV]) cause immune deficiency, encephalitis, and infectious anemia in mammals such as cattle, cat, goat, sheep, horse, and puma.

OBJECTIVE:

This study was designed and conducted with the main purpose of confirming the overall codon usage pattern of primate lentiviruses and exploring the evolutionary and genetic characteristics commonly or specifically expressed in HIV1, HIV2, and SIV.

METHODS:

The gag, pol, and env gene sequences of HIV1, HIV2, and SIV were analyzed to determine their evolutionary relationships, nucleotide compositions, codon usage patterns, neutrality, selection pressure (influence of mutational pressure and natural selection), and viral adaptation to human codon usage.

RESULTS:

A strong 'A' bias was confirmed in all three structural genes, consistent with previous findings regarding HIV. Notably, the ENC-GC3s plot and neutral evolution analysis showed that all primate lentiviruses were more affected by selection pressure than by mutation caused by the GC composition of the gene, consistent with prior reports regarding HIV1. The overall codon usage bias of pol was highest among the structural genes, while the codon usage bias of env was lowest. The virus groups showing high codon bias in all three genes were HIV1 and SIVcolobus. The codon adaptation index (CAI) and similarity D(A, B) values indicated that although there was a high degree of similarity to human codon usage in all three structural genes of HIV, this similarity was not caused by translation pressure. In addition, compared with HIV1, the codon usage of HIV2 is more similar to the human codon usage, but the overall codon usage bias is lower.

CONCLUSION:

The origin viruses of HIV (SIVcpz_gor and SIVsmm) exhibit greater similarity to human codon usage in the gag gene, confirming their robust adaptability to human codon usage. Therefore, HIV1 and HIV2 may have evolved to avoid human codon usage by selection pressure in the gag gene after interspecies transmission from SIV hosts to humans. By overcoming safety and stability issues, information from codon usage analysis will be useful for attenuated HIV1 vaccine development. A recoded HIV1 variant can be used as a vaccine vector or in immunotherapy to induce specific innate immune responses. Further research regarding HIV1 dinucleotide usage and codon pair usage will facilitate new approaches to the treatment of AIDS.

100 项与 HIV-1 RNA vaccine (HDT Bio) 相关的药物交易

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