Background Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased inciden...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2028436?articleTools=true

Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.

Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. The rapid development of a safe and effective ZIKV vaccine is a global health priority, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization with a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a strain of ZIKV involved in the outbreak in northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice. We produced DNA vaccines expressing ZIKV pre-membrane and envelope (prM-Env), as well as a series of deletion mutants. The prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV, as measured by absence of detectable viraemia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and depletion of CD4 and CD8 T lymphocytes in vaccinated mice did not abrogate this protection. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans is likely to be achievable.

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Vaccine protection against Zika virus from Brazil

Zika virus (ZIKV) was identified as a cause of congenital disease during the explosive outbreak in the Americas and Caribbean that began in 2015. Because of the ongoing fetal risk from endemic disease and travel-related exposures, a vaccine to prevent viremia in women of childbearing age and their partners is imperative. We found that vaccination with DNA expressing the premembrane and envelope proteins of ZIKV was immunogenic in mice and nonhuman primates, and protection against viremia after ZIKV challenge correlated with serum neutralizing activity. These data not only indicate that DNA vaccination could be a successful approach to protect against ZIKV infection, but also suggest a protective threshold of vaccine-induced neutralizing activity that prevents viremia after acute infection.

https://science.sciencemag.org/content/sci/354/6309/237.full.pdf

Rapid development of a DNA vaccine for Zika virus

West Nile virus (WNV) is an emerging neurotropic flavivirus that is transmitted to humans through the bite of an infected mosquito. WNV has disseminated broadly in the Western hemisphere and now poses a significant public health risk. The continuing spread of WNV, combined with the lack of specific therapeutics or vaccines to combat or prevent infection, imparts a pressing need to identify the viral and host processes that control the outcome of and immunity to WNV infection. Here, we provide an overview of recent research that has revealed the virus-host interface controlling WNV infection and immunity.

West Nile virus infection and immunity

Preclinical studies of viral vector–based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys.

https://science.sciencemag.org/content/sci/349/6245/320.full.pdf

Protective Efficacy of Adenovirus/Protein Vaccines Against SIV Challenges in Rhesus Monkeys

A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity To address this question, we used a nonhuman primate challenge model with simian immunodeficiency virus (SIV) We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies These analyses provide insight into the limited efficacy seen in HIV vaccine trials The analysis of multiple SIV vaccine regimens in macaques leads to the identification of a key two-amino-acid signature that confers resistance to neutralizing antibodies; a similar mechanism of immune escape is shown to operate in HIV and may explain the limited efficacy seen in HIV vaccine trials Clinical trials of human immunodeficiency virus-1 (HIV-1) vaccines have so far proved disappointing, achieving either low-level efficacy or zero protection Here Mario Roederer et al analyse the effects of multiple vaccine regimens in the macaque simian immunodeficiency virus (SIV) model and identify a key two-amino-acid signature that confers resistance to neutralizing antibodies A similar mechanism of immune escape is shown to operate in HIV, suggesting that this type of vaccine-elicited antibody response may explain the limited efficacy seen in HIV vaccine trials

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Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV

Background. West Nile virus (WNV) is a flavivirus that causes meningitis and encephalitis. There are no licensed vaccines to prevent WNV in humans. The safety and immunogenicity of a first-generation WNV DNA vaccine was demonstrated in a clinical trial and a similar DNA vaccine has been licensed for use in horses.

Methods. A DNA vaccine encoding the protein premembrane and the E glycoproteins of the NY99 strain of WNV under the transcriptional control of the CMV/R promoter was evaluated in an open-label study in 30 healthy adults. Half of the subjects were age 18–50 years and half were age 51–65 years. Immune responses were assessed by enzyme-linked immunosorbent assay, neutralization assays, intracellular cytokine staining, and ELISpot.

Results. The 3-dose vaccine regimen was safe and well tolerated. Vaccine-induced T cell and neutralizing antibody responses were detected in the majority of subjects. The antibody responses seen in the older age group were of similar frequency, magnitude, and duration as those seen in the younger cohort.

Conclusions. Neutralizing antibody responses to WNV were elicited by DNA vaccination in humans, including in older individuals, where responses to traditional vaccine approaches are often diminished. This DNA vaccine elicited T cell responses of greater magnitude when compared with an earlier-generation construct utilizing a CMV promoter.

 Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT00300417","term_id":"NCT00300417"}}NCT00300417.

/pdf/a-west-nile-virus-dna-vaccine-utilizing-a-modified-promoter-iwt0642ony.pdf

A West Nile Virus DNA Vaccine Utilizing a Modified Promoter Induces Neutralizing Antibody in Younger and Older Healthy Adults in a Phase I Clinical Trial

Wenjuan Gu

Papers

Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV

A West Nile Virus DNA Vaccine Utilizing a Modified Promoter Induces Neutralizing Antibody in Younger and Older Healthy Adults in a Phase I Clinical Trial