The Lancet Infectious Diseases
Mar 2016 Volume 16 Number 3 p265-384 e11-e33
http://www.thelancet.com/journals/laninf/issue/current

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Editorial
Zika virus in the dock
The Lancet Infectious Diseases
DOI: http://dx.doi.org/10.1016/S1473-3099(16)00085-2
Summary
In October, 2015, the Ministry of Health in Brazil reported an unexplained increase in cases of microcephaly, a congenital malformation normally associated with incomplete brain development, in newborn babies (4783 cases vs 150 in the previous year). The reported cases have caused widespread fear among pregnant women all over South and Central America, to the point that some nations such as Ecuador have recommended that their citizens postpone pregnancy to 2018, to give time to investigate the causes of the increase of microcephaly cases.

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Articles
H7N9 live attenuated influenza vaccine in healthy adults: a randomised, double-blind, placebo-controlled, phase 1 trial
Larisa Rudenko, Irina Isakova-Sivak, Anatoly Naykhin, Irina Kiseleva, Marina Stukova, Mariana Erofeeva, Daniil Korenkov, Victoria Matyushenko, Erin Sparrow, Marie-Paule Kieny
Summary
Background
H7N9 avian influenza viruses characterised by high virulence and presence of mammalian adaptation markers have pandemic potential. Specific influenza vaccines remain the main defence. We assessed the safety and immunogenicity of an H7N9 live attenuated influenza vaccine (LAIV) candidate in healthy adult volunteers.
Methods
We did a phase 1, double-blind, randomised, placebo-controlled trial in Saint Petersburg, Russia. Eligible participants were healthy adults aged 18–49 years. The participants were randomised 3:1 to receive live vaccine or placebo, according to a computer-generated randomisation scheme. Two doses of vaccine or placebo were administered intranasally 28 days apart, each followed by 7 day stays in hospital. Immune responses were assessed in nasal swabs, saliva, and serum specimens collected before and 28 days after each vaccine dose. The primary outcome was the safety profile. This trial is registered with ClinicalTrials.gov, number NCT02480101.
Findings
Between Oct 21, 2014, and Oct 31, 2014, 40 adults were randomised, of whom 39 (98%) were included in the per-protocol analysis (29 in the vaccine group and ten in the placebo group). The frequency of adverse events did not differ between the vaccine and placebo groups. Seroconversion of neutralising antibodies was seen in 14 participants after the first vaccine dose (48%, 95% CI 29·4–67·5) and 21 after the second vaccine dose (72%, 52·8–87·3). Immune responses were seen in 27 of 29 recipients (93%, 95% CI 77·2–99·2). Adverse effects were seen in 19 (63%) vaccine recipients and nine (90%) placebo recipients after the first dose and in nine (31%) and four (40%), respectively, after the second dose. These effects were mainly local and all were mild.
Interpretation
The H7N9 LAIV was well tolerated and safe and showed good immunogenicity.
Funding
WHO.

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Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study
Olga De Santis, Régine Audran, Emilie Pothin, Loane Warpelin-Decrausaz, Laure Vallotton, Grégoire Wuerzner, Camille Cochet, Daniel Estoppey, Viviane Steiner-Monard, Sophie Lonchampt, Anne-Christine Thierry, Carole Mayor, Robert T Bailer, Olivier Tshiani Mbaya, Yan Zhou, Aurélie Ploquin, Nancy J Sullivan, Barney S Graham, François Roman, Iris De Ryck, W Ripley Ballou, Marie Paule Kieny, Vasee Moorthy, François Spertini, Blaise Genton
Summary
Background
The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z).
Methods
We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18–65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 1010 viral particles), low-dose vaccine (2·5 × 1010 viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027.
Findings
Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 μg/mL (95% CI 41·1–63·3) in the high-dose group, 44·9 μg/mL (25·8–56·3) in the low-dose group, and 5·2 μg/mL (3·5–7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7–99·5), 96% (86·5–99·5), and 5% (0·1–24·9). Geometric mean concentrations decreased by day 180 to 25·5 μg/mL (95% CI 20·6–31·5) in the high-dose group, 22·1 μg/mL (19·3–28·6) in the low-dose group, and 3·2 μg/mL (2·4–4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses.
Interpretation
ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa.
Funding
Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.

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Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial
Xavier Sáez-Llorens, Ralf Clemens, Geert Leroux-Roels, José Jimeno, Sue Ann Costa Clemens, William C Weldon, M Steven Oberste, Natanael Molina, Ananda S Bandyopadhyay
Summary
Background
Following the proposed worldwide switch from trivalent oral poliovirus vaccine (tOPV) to bivalent types 1 and 3 OPV (bOPV) in 2016, inactivated poliovirus vaccine (IPV) will be the only source of protection against poliovirus type 2. With most countries opting for one dose of IPV in routine immunisation schedules during this transition because of cost and manufacturing constraints, optimisation of protection against all poliovirus types will be a priority of the global eradication programme. We assessed the immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine (mIPV2HD) in infants.
Methods
This observer-blind, comparative, randomised controlled trial was done in a single centre in Panama. We enrolled healthy infants who had not received any previous vaccination against poliovirus. Infants were randomly assigned (1:1) by computer-generated randomisation sequence to receive a single dose of either mIPV2HD or standard trivalent IPV given concurrently with a third dose of bOPV at 14 weeks of age. At 18 weeks, all infants were challenged with one dose of monovalent type 2 OPV (mOPV2). Primary endpoints were seroconversion and median antibody titres to type 2 poliovirus 4 weeks after vaccination with mIPV2HD or IPV; and safety (as determined by the proportion and nature of serious adverse events and important medical events for 8 weeks after vaccination). The primary immunogenicity analyses included all participants for whom a post-vaccination blood sample was available. All randomised participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02111135.
Findings
Between April 14 and May 9, 2014, 233 children were enrolled and randomly assigned to receive mIPV2HD (117 infants) or IPV (116 infants). 4 weeks after vaccination with mIPV2HD or IPV, seroconversion to poliovirus type 2 was recorded in 107 (93·0%, 95% CI 86·8–96·9) of 115 infants in the mIPV2HD group compared with 86 (74·8%, 65·8–82·4) of 115 infants in the IPV group (difference between groups 18·3%, 95% CI 5·0–31·1; p<0·0001), and median antibody titres against poliovirus type 2 were 181 (95% CI 72·0–362·0) in the mIPV2HD group and 36 (18·0–113·8) in the IPV group (difference between groups 98·8, 95% CI 60·7–136·9; p<0·0001). Serious adverse events were reported for six (5%) of 117 infants in the mIPV2HD group and seven (6%) of 116 infants in the IPV group during the 8-week period after vaccination; none were related to vaccination. No important medical events were reported.
Interpretation
Our findings lend support to the use of mIPV2HD as an option for stockpiling for outbreak response or primary protection in selected areas at risk for emergence of poliovirus type 2 during the next phase of the polio eradication plan.
Funding
Bill & Melinda Gates Foundation.