The Lancet
Dec 06, 2014 Volume 384 Number 9959 p1999 – 2082 e62
http://www.thelancet.com/journals/lancet/issue/current

Comment
Ebola virus disease: clinical care and patient-centred research
Ian Roberts, Anders Perner
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It is often stated that there are no proven therapies for Ebola virus disease but that potential treatments, including blood products, immune therapies, and antiviral drugs, are being evaluated.1 This view is inaccurate. Ebola virus disease is a febrile illness with severe gastrointestinal symptoms. Nausea, vomiting, and diarrhoea cause profound water and electrolyte depletion leading to circulatory collapse and death.2–4 Raised blood concentrations of urea and creatinine, indicators of severe dehydration and impaired renal function, are strongly correlated with mortality.

Comment
Chikungunya virus control: is a vaccine on the horizon?
Ann M Powers a
Vector-borne diseases such as malaria and dengue are among the most prevalent and important infectious diseases in the world. For example, WHO estimated that 40% of the world’s population is at risk of dengue virus infection and up to 100 million infections might occur annually.1 West Nile virus and Lyme disease are prominent examples of vector-borne diseases, with over 5600 and 31 000 human cases estimated, respectively, in 2012 in the USA alone.2, 3 Another arthropod-borne virus, chikungunya virus, which has caused over 2•5 million infections worldwide over the past decade, is spreading throughout the Americas and has recently been reported in the USA.4

Ideally, for both public health and economic reasons, options would be available for control of these infections before they cause large outbreaks. For chikungunya virus, on the island of La Reunion, about 300 000 cases were reported during the course of a 2005—06 outbreak, with an estimated economic cost of €43•9 million (in 2006 values).5, 6 The cost of a delayed response to introduction of a new arboviral disease could be as much as 346 times as high as the cost of preparedness through surveillance for the outbreak event.7 Additional preparedness efforts, including the availability of effective and safe vaccines, could further reduce the scope and harms of an eventual outbreak.

A chikungunya virus vaccine candidate was developed in the USA before the large outbreaks that started in 2004 in coastal Kenya. Phase 2 clinical trials were done on the live-attenuated vaccine candidate8 before further development was discontinued because of an absence of funding and questions regarding the eventual marketing of the vaccine.9 However, with the continued expansion of the chikungunya epidemic, Lee-Jah Chang and colleagues10 have reinvigorated chikungunya virus vaccine development with a report in The Lancet detailing the completion of a phase 1 clinical trial on the VRC virus-like particle (VLP) vaccine candidate, VRC-CHKVLP059-00-VP. This dose-escalation, open-label clinical trial included 25 participants and assessed the safety, tolerability, and immunogenicity of the candidate vaccine administered on weeks 0, 4, and 20 at ascending doses of 10 μg (n=5), 20 μg (n=10), and 40 μg (n=10). This VLP vaccine, which had previously been shown to protect non-human primates against virus infection,11 elicited antibody development in all participants.10 Importantly, neutralising antibodies persisted for at least 6 months in all participants in all dose groups, which suggests that the vaccine could provide long-term protection against the virus.

The development of a VLP vaccine is a new approach in vaccine technology—one that should result in a safer option than more traditional approaches such as killed vaccines or live-attenuated candidates. A VLP contains the outer structural proteins of the virus—the ones that would typically be recognised by the immune system. None of the viral genetic material is present, and so no live virus could ever be generated. The absence of any live virus also provides a manufacturing advantage because no high-containment facilities would be needed for production. In this study,10 no serious adverse events were reported and tenderness at the injection site was the only localised symptom (present in nine of 25 participants). Mild systemic reactions including headache, malaise, myalgia, and nausea were reported in ten participants. Overall, the safety data reported suggest that the vaccine would be well tolerated.

Additionally, the investigators noted increasing concentrations of antibodies after booster doses. All participants were antibody positive after the second dose, with the antibody concentrations reaching a peak 4 weeks after the third dose. Although multiple doses can be a challenge in developing countries, alternative formulations of the VLP might increase immunogenicity. For example, inclusion of an adjuvant could lead to equally high concentrations of antibody in fewer doses. Importantly, the concentrations of antibodies detected in participants at week 4—ie, after the initial dose—seemed to be similar to those in patients who had recovered from wild-type infections. Another important aspect of the study was the inclusion of several genotypes, or variants, in the antibody analysis. The VLP vaccine generated antibodies against these distinct variants, suggesting that the vaccine would be effective against any strain of the virus, including the type circulating in the Americas.

Although this VLP vaccine candidate exhibits a range of properties that suggest it would be a good vaccine option, there is always concern about whether a vaccine for a vector-borne virus will be licensed. Development of vaccines for orphan agents is challenging because the market might not be large enough to justify the investment. The cost of development of a vaccine—from preclinical studies to vaccine registration—is estimated to be US$200—500 million.12 Yet, even with this need for substantial funding, vaccines are still the most cost-effective strategy for disease prevention.13 Despite these limitations, there is optimism for vaccine development, with the findings that a vaccine for another vector-borne disease, dengue, could be made available at an affordable price,14 and policy makers in affected countries have expressed interest in public-sector use of a dengue vaccine.15 In view of the burden of chikungunya outbreaks, which have affected up to 63% of local populations in a matter of months,16 the continued development of this VLP vaccine candidate, along with other vaccine options, should be encouraged.

Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial
Lee-Jah Chang MD a †, Kimberly A Dowd PhD b †, Floreliz H Mendoza RN a, Jamie G Saunders BSN a, Sandra Sitar MSc a, Sarah H Plummer NP a, Galina Yamshchikov MSc a, Uzma N Sarwar MD a, Zonghui Hu PhD c, Mary E Enama PA-C a, Robert T Bailer PhD a, Richard A Koup MD a, Richard M Schwartz PhD a, Wataru Akahata PhD a, Gary J Nabel MD a, John R Mascola MD a, Theodore C Pierson PhD b, Barney S Graham MD a, Dr Julie E Ledgerwood DO a, the VRC 311 Study Team
Summary
Background
Chikungunya virus—a mosquito-borne alphavirus—is endemic in Africa and south and southeast Asia and has recently emerged in the Caribbean. No drugs or vaccines are available for treatment or prevention. We aimed to assess the safety, tolerability, and immunogenicity of a new candidate vaccine.
Methods
VRC 311 was a phase 1, dose-escalation, open-label clinical trial of a virus-like particle (VLP) chikungunya virus vaccine, VRC-CHKVLP059-00-VP, in healthy adults aged 18—50 years who were enrolled at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Participants were assigned to sequential dose level groups to receive vaccinations at 10 μg, 20 μg, or 40 μg on weeks 0, 4, and 20, with follow-up for 44 weeks after enrolment. The primary endpoints were safety and tolerability of the vaccine. Secondary endpoints were chikungunya virus-specific immune responses assessed by ELISA and neutralising antibody assays. This trial is registered with ClinicalTrials.gov, NCT01489358.
Findings
25 participants were enrolled from Dec 12, 2011, to March 22, 2012, into the three dosage groups: 10 μg (n=5), 20 μg (n=10), and 40 μg (n=10). The protocol was completed by all five participants at the 10 μg dose, all ten participants at the 20 μg dose, and eight of ten participants at the 40 μg dose; non-completions were for personal circumstances unrelated to adverse events. 73 vaccinations were administered. All injections were well tolerated, with no serious adverse events reported. Neutralising antibodies were detected in all dose groups after the second vaccination (geometric mean titres of the half maximum inhibitory concentration: 2688 in the 10 μg group, 1775 in the 20 μg group, and 7246 in the 40 μg group), and a significant boost occurred after the third vaccination in all dose groups (10 μg group p=0•0197, 20 μg group p<0•0001, and 40 μg group p<0•0001). 4 weeks after the third vaccination, the geometric mean titres of the half maximum inhibitory concentration were 8745 for the 10 μg group, 4525 for the 20 μg group, and 5390 for the 40 μg group.
Interpretation
The chikungunya VLP vaccine was immunogenic, safe, and well tolerated. This study represents an important step in vaccine development to combat this rapidly emerging pathogen. Further studies should be done in a larger number of participants and in more diverse populations.
Funding
Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.
Seminar
Hepatitis B virus infection
Christian Trépo, Henry L Y Chan, Anna Lok
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Hepatitis B virus infection is a major public health problem worldwide; roughly 30% of the world’s population show serological evidence of current or past infection. Hepatitis B virus is a partly double-stranded DNA virus with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and, although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence.
Hypothesis
The immune response and within-host emergence of pandemic influenza virus
Dr Leslie A Reperant PhD a b, Prof Thijs Kuiken PhD a, Prof Bryan T Grenfell PhD c d, Prof Albert D M E Osterhaus PhD a b
Summary
Zoonotic influenza viruses that are a few mutations away from pandemic viruses circulate in animals, and can evolve into airborne-transmissible viruses in human beings. Paradoxically, such viruses only occasionally emerge in people; the four influenza pandemics that occurred in the past 100 years were caused by zoonotic viruses that acquired efficient transmissibility. Emergence of a pandemic virus in people can happen when transmissible viruses evolve in individuals with zoonotic influenza and replicate to titres allowing transmission. We postulate that this step in the genesis of a pandemic virus only occasionally occurs in human beings, because the immune response triggered by zoonotic influenza virus also controls transmissible mutants that emerge during infection. Therefore, an impaired immune response might be needed for within-host emergence of a pandemic virus and replication to titres allowing transmission. Immunocompromised individuals—eg, those with comorbidities, of advanced age, or receiving immunosuppressive treatment—could be at increased risk of generating transmissible viruses and initiating chains of human-to-human infection.