The race to develop Ebola vaccines will soon enter a new phase that may bring answers to the most important question: Do they actually work? In as little as 4 weeks, tests could begin in West Africa in people at risk of contracting Ebola with one of two vaccines that have moved forward at an unprecedented pace, said Marie-Paule Kieny, an assistant director-general at the World Health Organization (WHO), at a press conference today in Geneva, Switzerland.But a new issue is complicating the studies. The number of new Ebola cases has declined unexpectedly fast in recent months, especially in Liberia. That’s great news, but it will make it harder to show that a vaccine works, because the studies need a minimum number of new infections to prove that it offers protection from the disease.So far, so-called phase I tests have given experimental Ebola vaccines to healthy volunteers not at risk for Ebola, assessing safety and immune responses. Last year, a WHO panel decided that given the huge threat, it would be ethical to jump straight from these small studies to phase III trials, which test for efficacy. Phase II studies—which evaluate safety and immune responses in a larger number of people—will start simultaneously.Sign up for our daily newsletterGet more great content like this delivered right to you!Country *AfghanistanAland IslandsAlbaniaAlgeriaAndorraAngolaAnguillaAntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustraliaAustriaAzerbaijanBahamasBahrainBangladeshBarbadosBelarusBelgiumBelizeBeninBermudaBhutanBolivia, Plurinational State ofBonaire, Sint Eustatius and SabaBosnia and HerzegovinaBotswanaBouvet IslandBrazilBritish Indian Ocean TerritoryBrunei DarussalamBulgariaBurkina FasoBurundiCambodiaCameroonCanadaCape VerdeCayman IslandsCentral African RepublicChadChileChinaChristmas IslandCocos (Keeling) IslandsColombiaComorosCongoCongo, The Democratic Republic of theCook IslandsCosta RicaCote D’IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDenmarkDjiboutiDominicaDominican RepublicEcuadorEgyptEl SalvadorEquatorial GuineaEritreaEstoniaEthiopiaFalkland Islands (Malvinas)Faroe IslandsFijiFinlandFranceFrench GuianaFrench PolynesiaFrench Southern TerritoriesGabonGambiaGeorgiaGermanyGhanaGibraltarGreeceGreenlandGrenadaGuadeloupeGuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHeard Island and Mcdonald IslandsHoly See (Vatican City State)HondurasHong KongHungaryIcelandIndiaIndonesiaIran, Islamic Republic ofIraqIrelandIsle of ManIsraelItalyJamaicaJapanJerseyJordanKazakhstanKenyaKiribatiKorea, Democratic People’s Republic ofKorea, Republic ofKuwaitKyrgyzstanLao People’s Democratic RepublicLatviaLebanonLesothoLiberiaLibyan Arab JamahiriyaLiechtensteinLithuaniaLuxembourgMacaoMacedonia, The Former Yugoslav Republic ofMadagascarMalawiMalaysiaMaldivesMaliMaltaMartiniqueMauritaniaMauritiusMayotteMexicoMoldova, Republic ofMonacoMongoliaMontenegroMontserratMoroccoMozambiqueMyanmarNamibiaNauruNepalNetherlandsNew CaledoniaNew ZealandNicaraguaNigerNigeriaNiueNorfolk IslandNorwayOmanPakistanPalestinianPanamaPapua New GuineaParaguayPeruPhilippinesPitcairnPolandPortugalQatarReunionRomaniaRussian FederationRWANDASaint Barthélemy Saint Helena, Ascension and Tristan da CunhaSaint Kitts and NevisSaint LuciaSaint Martin (French part)Saint Pierre and MiquelonSaint Vincent and the GrenadinesSamoaSan MarinoSao Tome and PrincipeSaudi ArabiaSenegalSerbiaSeychellesSierra LeoneSingaporeSint Maarten (Dutch part)SlovakiaSloveniaSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSvalbard and Jan MayenSwazilandSwedenSwitzerlandSyrian Arab RepublicTaiwanTajikistanTanzania, United Republic ofThailandTimor-LesteTogoTokelauTongaTrinidad and TobagoTunisiaTurkeyTurkmenistanTurks and Caicos IslandsTuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVenezuela, Bolivarian Republic ofVietnamVirgin Islands, BritishWallis and FutunaWestern SaharaYemenZambiaZimbabweI also wish to receive emails from AAAS/Science and Science advertisers, including information on products, services and special offers which may include but are not limited to news, careers information & upcoming events.Required fields are included by an asterisk(*)At a WHO meeting held yesterday on Ebola vaccines, an international group of experts discussed the latest developments, which Kieny outlined at the press conference:A vaccine made by GlaxoSmithKline (GSK)—which contains a chimp adenovirus laced with a gene that codes for the Ebola surface protein—has enrolled all the volunteers in its phase I trial; the company is now analyzing the data in order to decide the best dose for the phase III study and whether to give it once or twice. That analysis should take no more than 4 weeks, and phase III trials could begin soon after. The company could have “a few million doses” of the vaccine produced by mid-2015, Kieny added, although that number will depend on the required dose. Sierra Leone will do a so-called stepped-wedge design, in which some groups receive the vaccine earlier than others, and efficacy is shown if the former group has fewer infections than the latter. (This design takes longer to produce statistically significant answers, but is deemed more ethical by some because all participants eventually receive the vaccine.) Kieny said the study will enroll some 6000 front-line Ebola workers and will probably test the vaccine that triggers the most robust immune responses in the phase I studies. A vaccine initially made by NewLink Genetics but now manufactured by Merck still needs to enroll more volunteers in its phase I studies. This vaccine uses a livestock virus called VSV, rather than the chimp virus, as the vector to carry the Ebola gene. One study was halted after some participants developed arthritislike symptoms, but it later resumed. The company can produce tens of millions of doses in 2015, Kieny said.Kieny also discussed the trial designs adopted for each of the three countries hardest hit by Ebola. The methodology and the ethics of the vaccine studies have been debated extensively, and in the end, the three countries will each use distinct designs:Liberia will do a randomized, controlled trial—the gold standard in drug and vaccine testing—with three arms, each including about 9000 people. One will receive the GSK vaccine, the second the Merck vaccine, and the third will form a control group that receives neither. Although the original plan was to target front-line Ebola workers such as doctors, nurses, and ambulance drivers, researchers now plan to recruit among the Liberian population at large. (Very few health care workers have become infected with Ebola recently.) Guinea will test ring vaccination—a strategy used to help eradicate smallpox— in which a group of people around an Ebola patient is vaccinated. This variation on the stepped-wedge design will have two arms, each with some 90 “rings,” with an average of 50 vaccinees per ring, meaning a total of 9000 trial participants. In one arm, the vaccine will be given early, whereas the rings in the other arm would receive the vaccine later. In addition, front-line workers will receive the vaccine in a so-called observational study that has no control group.On Tuesday, a third company, Johnson & Johnson, announced the launch of its own Ebola vaccine trial. The phase I trial, conducted by the University of Oxford in the United Kingdom, tests two shots in what’s called a prime-boost strategy. The first shot, developed by Crucell in the Netherlands, uses a human adenovirus vector. The boost, which participants will receive 1 or 2 months later, is produced by Bavarian Nordic in Denmark and uses a modified version of the old smallpox vaccine, MVA, as the vector. The company has begun scouting for phase III test sites in the affected countries, Kieny said.A third candidate is welcome, she added. Based on results so far, Johnson & Johnson’s two-pronged vaccine would take longer to trigger robust immunity, but the protection might last longer; that might make it suitable for vaccinating people likely to become exposed to Ebola in the future, such as health care workers. Faster acting vaccines might be of more use in stanching outbreaks, where long-lasting protection isn’t as important.Whereas the other two vaccines need to be deep-frozen, Johnson & Johnson’s products will keep at temperatures between 2°C and 8°C, she said, a major advantage in remote areas. Tens of millions of doses of each of the vaccine’s two components can be produced in 2015, Kieny said.First results for the phase III studies can be expected after 6 months or so. Independent data and safety monitoring boards will keep a close watch on the trials and review the blinded data as they come in; aside from side effects, a board can stop a study early if significant success surfaces or it becomes clear that the trial doesn’t have the statistical power to provide a clear answer.But the dramatic drop in cases in Liberia, although reason to celebrate, could throw a spanner in the works, because it’s harder to demonstrate that a vaccine protects people when fewer people are at risk. If other efforts to rein in the virus make significant headway, it could further compromise the study’s power. Kieny acknowledged that risk and said Liberia—where new cases have slowed down to a trickle—has decided to recruit more participants to increase the odds that the trial will end with a firm conclusion.*The Ebola Files: Given the current Ebola outbreak, unprecedented in terms of number of people killed and rapid geographic spread, Science and Science Translational Medicinehave made a collection of research and news articles on the viral disease freely available to researchers and the general public.