A Single and Un-Adjuvanted Dose of a Chimpanzee Adenovirus-Vectored Vaccine against Chikungunya Virus Fully Protects Mice from Lethal Disease

The mosquito-borne chikungunya virus (CHIKV) has become a major global health problem. Upon infection, chikungunya fever (CHIKF) can result in long-term joint pain and arthritis, and despite intense research, no licensed vaccine for CHIKV is available. We have developed two recombinant chimpanzee adenovirus-vectored vaccines (ChAdOx1) that induce swift and robust anti-CHIKV immune responses with a single dose, without the need for adjuvants or booster vaccines. Here, we report the vaccines’ protective efficacies against CHIKV infection in a lethal A129 mouse model. Our results indicate that a single, un-adjuvanted ChAdOx1 Chik or ChAdOx1 Chik ΔCap dose provided complete protection against a lethal virus challenge and prevented CHIKV-associated severe inflammation. These candidate vaccines supported survival equal to the attenuated 181/25 CHIKV reference vaccine but without the vaccine-related side effects, such as weight loss. Vaccination with either ChAdOx1 Chik or ChAdOx1 Chik ΔCap resulted in high titers of neutralizing antibodies that are associated with protection, indicating that the presence of the capsid within the vaccine construct may not be essential to afford protection under the conditions tested. We conclude that both replication-deficient ChAdOx1 Chik vaccines are safe even when used in A129 mice and afford complete protection from a lethal challenge.

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Attenuated Vesicular Stomatitis Viruses as Vaccine Vectors

Journal of Virology ◽

10.1128/jvi.73.5.3723-3732.1999 ◽

1999 ◽

Vol 73 (5) ◽

pp. 3723-3732 ◽

Cited By ~ 190

Author(s):

Anjeanette Roberts ◽

Linda Buonocore ◽

Ryan Price ◽

John Forman ◽

John K. Rose

Keyword(s):

Influenza Virus ◽

Vesicular Stomatitis Virus ◽

Neutralizing Antibodies ◽

Intranasal Administration ◽

Complete Protection ◽

Lethal Challenge ◽

Virus Challenge ◽

Influenza Virus Hemagglutinin ◽

Vesicular Stomatitis ◽

Ha Protein

ABSTRACT We showed previously that a single intranasal vaccination of mice with a recombinant vesicular stomatitis virus (VSV) expressing an influenza virus hemagglutinin (HA) protein provided complete protection from lethal challenge with influenza virus (A. Roberts, E. Kretzschmar, A. S. Perkins, J. Forman, R. Price, L. Buonocore, Y. Kawaoka, and J. K. Rose, J. Virol. 72:4704–4711, 1998). Because some pathogenesis was associated with the vector itself, in the present study we generated new VSV vectors expressing HA which are completely attenuated for pathogenesis in the mouse model. The first vector has a truncation of the cytoplasmic domain of the VSV G protein and expresses influenza virus HA (CT1-HA). This nonpathogenic vector provides complete protection from lethal influenza virus challenge after intranasal administration. A second vector with VSV G deleted and expressing HA (ΔG-HA) is also protective and nonpathogenic and has the advantage of not inducing neutralizing antibodies to the vector itself.

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Adenovirus vectored IFN-α protects mice from lethal challenge of Chikungunya virus infection

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008910 ◽

2020 ◽

Vol 14 (12) ◽

pp. e0008910

Author(s):

Huixin Chen ◽

Nyo Min ◽

Luyao Ma ◽

Chee-Keng Mok ◽

Justin Jang Hann Chu

Keyword(s):

Single Dose ◽

Chikungunya Virus ◽

Lethal Dose ◽

Inhibitory Effect ◽

Dependent Manner ◽

Chikv Infection ◽

Lethal Challenge ◽

Virus Challenge ◽

Multiple Organs

Chikungunya virus (CHIKV) is a mosquito-borne pathogen that is responsible for numerous large and geographical epidemics, causing millions of cases. However, there is no vaccine or therapeutics against CHIKV infection available. Interferon-alpha (IFN-α) has been shown to produce potent antiviral responses during viral infection. Herein we demonstrated the use of an adenovirus-vectored expressed mouse IFN-α (mDEF201) as a prophylactic and therapeutic treatment against CHIKV in vivo. 6-day-old BALB/c mice were pre- or post-treated intranasally with single dose of mDEF201 at 5 x 106 PFU per mouse and challenged with lethal dose of CHIKV. Complete survival protection was observed in mice upon a single dose of mDEF201 administration 1 days prior to virus challenge. Viral load in the serum and multiple organs were significantly reduced upon mDEF201 administration in a dose dependent manner as compare with adenovirus 5 vector placebo set. Histological analysis of the mice tissue revealed that mDEF201 could significantly reduce the tissue morphological abnormities, mainly infiltration of immune cells and muscle fibre necrosis caused by CHIKV infection. In addition, administration of mDEF201 at 6 hours post CHIKV challenge also showed promising inhibitory effect against viral replication and dissemination. In conclusion, single-dose of intranasal administration with mDEF201 as a prophylactic or therapeutic agent within 6 hours post CHIKV infection is highly protective against a lethal challenge of CHIKV in the murine model.

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COVID-19: Mechanisms of Vaccination and Immunity

Vaccines ◽

10.3390/vaccines8030404 ◽

2020 ◽

Vol 8 (3) ◽

pp. 404 ◽

Cited By ~ 1

Author(s):

Daniel E. Speiser ◽

Martin F. Bachmann

Keyword(s):

Immune Responses ◽

Clinical Management ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Public Life ◽

High Affinity ◽

Vaccination Strategies ◽

Detailed Evaluation ◽

Pros And Cons

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world’s population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.

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Persistent Replication of a Chikungunya Virus Replicon in Human Cells Is Associated with Presence of Stable Cytoplasmic Granules Containing Nonstructural Protein 3

Journal of Virology ◽

10.1128/jvi.00477-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 10

Author(s):

Roland Remenyi ◽

Yanni Gao ◽

Ruth E. Hughes ◽

Alistair Curd ◽

Carsten Zothner ◽

...

Keyword(s):

Chronic Disease ◽

Chikungunya Virus ◽

Protein Complexes ◽

Nonstructural Protein ◽

Viral Proteins ◽

Human Cells ◽

Chikv Infection ◽

Cytoplasmic Granules ◽

Nonstructural Protein 3

ABSTRACTChikungunya virus (CHIKV), a mosquito-borne human pathogen, causes a disabling disease characterized by severe joint pain that can persist for weeks, months, or even years in patients. The nonstructural protein 3 (nsP3) plays essential roles during acute infection, but little is known about the function of nsP3 during chronic disease. Here, we used subdiffraction multicolor microscopy for spatial and temporal analysis of CHIKV nsP3 within human cells that persistently replicate replicon RNA. Round cytoplasmic granules of various sizes (i) contained nsP3 and stress granule assembly factors 1 and 2 (G3BP1/2), (ii) were next to double-stranded RNA foci and nsP1-positive structures, and (iii) were close to the nuclear membrane and the nuclear pore complex protein Nup98. Analysis of protein turnover and mobility by live-cell microscopy revealed that the granules could persist for hours to days, accumulated newly synthesized protein, and moved through the cytoplasm at various speeds. The granules also had a static internal architecture and were stable in cell lysates. Refractory cells that had cleared the noncytotoxic replicon regained the ability to respond to arsenite-induced stress. In summary, nsP3 can form uniquely stable granular structures that persist long-term within the host cell. This continued presence of viral and cellular protein complexes has implications for the study of the pathogenic consequences of lingering CHIKV infection and the development of strategies to mitigate the burden of chronic musculoskeletal disease brought about by a medically important arthropod-borne virus (arbovirus).IMPORTANCEChikungunya virus (CHIKV) is a reemerging alphavirus transmitted by mosquitos and causes transient sickness but also chronic disease affecting muscles and joints. No approved vaccines or antivirals are available. Thus, a better understanding of the viral life cycle and the role of viral proteins can aid in identifying new therapeutic targets. Advances in microscopy and development of noncytotoxic replicons (A. Utt, P. K. Das, M. Varjak, V. Lulla, A. Lulla, A. Merits, J Virol 89:3145–3162, 2015,https://doi.org/10.1128/JVI.03213-14) have allowed researchers to study viral proteins within controlled laboratory environments over extended durations. Here we established human cells that stably replicate replicon RNA and express tagged nonstructural protein 3 (nsP3). The ability to track nsP3 within the host cell and during persistent replication can benefit fundamental research efforts to better understand long-term consequences of the persistence of viral protein complexes and thereby provide the foundation for new therapeutic targets to control CHIKV infection and treat chronic disease symptoms.

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Chapter 14: Prevention: vaccines and immunoglobulins

Tick-borne encephalitis - The Book ◽

10.33442/26613980_14-4 ◽

2021 ◽

Author(s):

Eva-Maria Pöllabauer ◽

Herwig Kollaritsch

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Western Europe ◽

Surrogate Marker ◽

Booster Vaccination ◽

Post Exposure Prophylaxis ◽

Pediatric Formulation ◽

The One ◽

Exposure Prophylaxis

Worldwide there are 6 different TBE vaccines – two from Western Europe, three from Russia and one from China. The two western European vaccines and one of the Russian vaccines have an adult and a pediatric formulation. The products names are FSME IMMUN and FSME-IMMUN Junior; Encepur adults and Encepur children, Klesch-E-Vac, EnceVir and EnceVir Neo, Dry lyophilized TBE Moscow and Sen Tai Bao. All TBE vaccines except the one from China have similar but not identical immunization schedules with primary immunization (>3 doses) and regular booster vaccinations. For FSME-IMMUN, Encepur and EnceVir rapid immunization schedules are also licensed. The Chinese vaccine is given with 2 primary doses 2 weeks apart followed by annual boosters. All vaccines induce significant immune responses. In the absence of a formal correlate of protection, the presence of neutralizing antibodies is used as a surrogate marker for protection. Recent clinical studies show long-term seropersistence of TBE antibodies after the first booster vaccination (dose 4) with the two European vaccines. An effectiveness of approximately 99% (years 2000–2006) and 98.7% (years 2000-2011) was calculated for regularly vaccinated persons in Austria, a country with established high vaccination uptake. Whereas in Western Europe post-exposure prophylaxis with immunoglobulins was discontinued in the late 1990s, in the highly endemic regions of Russia it continues to be common practice. Both – FSME-IMMUN and Encepur are well tolerated with a well-established safety profile. TBE-Moscow and EnceVir appear to be somewhat more reactogenic.

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Serological Responses in Patients Infected with Mayaro Virus and Evaluation of Cross-Protective Responses against Chikungunya Virus

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.21-0579 ◽

2021 ◽

Author(s):

Nathen E. Bopp ◽

Kara J. Jencks ◽

Crystyan Siles ◽

Carolina Guevara ◽

Stalin Vilcarromero ◽

...

Keyword(s):

Latin America ◽

South America ◽

Neutralizing Antibodies ◽

Chikungunya Virus ◽

Neutralization Test ◽

Close Relative ◽

Previous Exposure ◽

Chikv Infection ◽

The Caribbean ◽

Mayaro Virus

Mayaro virus (MAYV) is an alphavirus endemic to both Latin America and the Caribbean. Recent reports have questioned the ability of MAYV and its close relative, Chikungunya virus (CHIKV), to generate cross-reactive, neutralizing antibodies to one another. Since CHIKV was introduced to South America in 2013, discerning whether individuals have cross-reactive antibodies or whether they have had exposures to both viruses previously has been difficult. Using samples obtained from people infected with MAYV prior to the introduction of CHIKV in the Americas, we performed neutralizing assays and observed no discernable neutralization of CHIKV by sera from patients previously infected with MAYV. These data suggest that a positive CHIKV neutralization test cannot be attributed to prior exposure to MAYV and that previous exposure to MAYV may not be protective against a subsequent CHIKV infection.

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A Replicating Single-Cycle Adenovirus Vaccine Effective against Clostridium difficile

Vaccines ◽

10.3390/vaccines8030470 ◽

2020 ◽

Vol 8 (3) ◽

pp. 470

Author(s):

William E. Matchett ◽

Stephanie Anguiano-Zarate ◽

Goda Baddage Rakitha Malewana ◽

Haley Mudrick ◽

Melissa Weldy ◽

...

Keyword(s):

Clostridium Difficile ◽

Neutralizing Antibodies ◽

Antibody Responses ◽

Complete Protection ◽

Single Cycle ◽

Toxin B ◽

Toxin Binding ◽

Binding Domains ◽

Binding Antibody

Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

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Effects of Chikungunya virus immunity on Mayaro virus disease and epidemic potential

Scientific Reports ◽

10.1038/s41598-019-56551-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Emily M. Webb ◽

Sasha R. Azar ◽

Sherry L. Haller ◽

Rose M. Langsjoen ◽

Candace E. Cuthbert ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Chikungunya Virus ◽

Semliki Forest Virus ◽

Virus Disease ◽

Cross Protection ◽

Health Concern ◽

Antigenic Relationship ◽

Wild Type ◽

Chikv Infection ◽

Mayaro Virus

AbstractMayaro virus (MAYV) causes an acute febrile illness similar to that produced by chikungunya virus (CHIKV), an evolutionary relative in the Semliki Forest virus complex of alphaviruses. MAYV emergence is typically sporadic, but recent isolations and outbreaks indicate that the virus remains a public health concern. Given the close phylogenetic and antigenic relationship between CHIKV and MAYV, and widespread distribution of CHIKV, we hypothesized that prior CHIKV immunity may affect MAYV pathogenesis and/or influence its emergence potential. We pre-exposed immunocompetent C57BL/6 and immunocompromised A129 or IFNAR mice to wild-type CHIKV, two CHIKV vaccines, or a live-attenuated MAYV vaccine, and challenged with MAYV. We observed strong cross-protection against MAYV for mice pre-exposed to wild-type CHIKV, and moderately but significantly reduced cross-protection from CHIKV-vaccinated animals. Immunity to other alphavirus or flavivirus controls provided no protection against MAYV disease or viremia. Mechanistic studies suggested that neutralizing antibodies alone can mediate this protection, with T-cells having no significant effect on diminishing disease. Finally, human sera obtained from naturally acquired CHIKV infection cross-neutralized MAYV at high titers in vitro. Altogether, our data suggest that CHIKV infection can confer cross-protective effects against MAYV, and the resultant reduction in viremia may limit the emergence potential of MAYV.

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