Towards a human lassa fever vaccine

Rev. Med. Virol. 2001; 11: 331–341.
Towards a human Lassa fever vaccineS. P. Fisher-Hoch* and J. B. McCormickUniversity of Texas School of Public Health at Brownsville, 80 Fort Brown, SET. B 1.334, Brownsville,Texas 78520, USA Arenaviruses, such as Lassa fever, establish chronic infections in rodents, leading to incidental transmission tohumans. Lassa fever is a clinically severe disease, yet the absence of second attacks implies life-long immunity.
The aim of this review is to consider whether such immunity could be provided by vaccines. The SouthAmerican arenaviruses are controlled by neutralising antibody and a clinical trial of live, attenuated vaccine forArgentinian haemorrhagic fever provided 84% protection. In contrast, there is no evidence for protective humoralimmunity against Old World arenaviruses which are controlled by cell-mediated immune responses.
Nevertheless, vaccination with Lassa glycoproteins can protect monkeys from disease, implying that protectionmay be achievable, even though the immunological mechanisms are distinct. Recombinant vaccinia virusesexpressing various forms of Lassa glycoproteins can protect both guinea-pigs and primates, while additionalprotective responses can be mounted against nucleocapsid genes. However, vaccines based upon vacciniaconstructs are no longer tenable for African populations with a high seroprevalence of HIV infection. Thescientific challenge now remains to find alternative methods of delivering T-cell immunity against glycoproteinsfrom Lassa virus in ways which can overcome the local economic and political hurdles to vaccine development.
Copyright # 2001 John Wiley & Sons, Ltd.
successfulAfrican rat, Mastomys natalensis, has adapted to a peridomestic life in village houses in Lassa fever is a viralhaemorrhagic fever caused West Africa. [4]. Accidentalhuman exposure to by an arenavirus, first described in West Africa in the virus is therefore frequent. With the human the 1950s, although the virus was not isolated population explosion in the endemic area over the until1969 [1,2]. Arenaviruses produce mostl past 50 years or so, the opportunities for infection silent, persistent infection in rodents, and their with this virus, and thus disease, have increased origin is thought to date back to the evolution of exponentially. Among the haemorrhagic fevers, different rodent species, perhaps as much as 9 Lassa fever affects by far the largest number of million years ago [3]. Accidental human infection, people, creating a geographical patchwork of ende- therefore, must have been happening for as long mic foci encompassing a population of perhaps 180 as virus infected rodents and humans shared million from Guinea to eastern Nigeria.
habitats. The principalrisk to humans from Lassa The co-speciation of arenaviruses and rodents has recently been confirmed by molecular ana-lyses. Using a sequence near the 3k end of the *Corresponding author: Dr S. P. Fisher-Hoch, University of Texas nucleoprotein gene, analysis confirms the histor- School of Public Health at Brownsville, 80 Fort Brown, SET.B1. 334,Brownsville, Texas 78520, USA. E-mail: sfi[email protected] ical division of arenaviruses (originally based ongeographicaldistribution and antigenic typing) into Old World (LCMV, LASV), which includes AHV, Argentinian haemorrhagic fever; BSL, biosafety level; EPI,expanded programme of immunisation; GPC, glycoprotein precursor; Lassa virus, Mopeia and Lymphocytic Chorio- LASV, Lassa virus; LCMV, lymphocytic choriomeningitis virus; N, nucleoprotein; UN, United Nations; V-LSG, vaccinia recombinant (Tacaribe complex) viruses, which include at expressing the full length glycoprotein; V-LSG1, vaccinia recombi-nant expressing glycoprotein 1; V-LSG2, vaccinia recombinant least four viruses highly pathogenic for humans expressing glycoprotein 2; V-LSG/N, vaccinia recombinant expres- [5]. The LCMV, LASV complex viruses are mono- sing the glycoprotein and nucleoprotein; V-LSGPC, vaccinia phyletic with three distinct lineages, one of which recombinant expressing the glycoprotein precursor; V-LSN, vacciniarecombinant expressing the nucleoprotein contains Lassa, Mopeia and Mobala viruses [6].
Copyright # 2001 John Wiley & Sons, Ltd.
Mopeia comes from southern Africa and Mobala about 30% of adult deaths. Lassa fever also affects from centralAfrica, and both are carried by children, with considerable mortality in infants related Mastomys species [7]. Both can infect humans, but are apparently unable to cause Person-to-person spread of Lassa virus occurs significant clinical disease. Experimental infection within homes as well as in hospitals. This is where of non-human primates with Mopeia virus is also the major outbreaks have been and continue to be.
silent. As will be discussed later, Mopeia virus has The outbreaks are associated with inadequate been proposed as a potentiallive-attenuated Lassa disinfection and direct contact with infected vaccine, and it is certainly effective as such in non- blood and contaminated needles. Increasing and indiscriminate use of needles for intravenous therapy, or intramuscular injections in West pathogenicity for humans does not appear to African hospitals along with inadequate needle be monophyletic, suggesting that virulence in and syringe sterilisation has led to large-scale arenaviruses is the result of independent evolu- epidemics. These epidemics can be devastating, tionary events [5]. These conclusions are based on resulting in the deaths not only of patients but also S-segment sequence analysis, but virulence may medicalstaff, surgeons, nurses and other scarce not in fact be associated with the S segment.
Indeed, there are data suggesting that virulence Lassa fever is an increasing threat. It now affects determinants in LCMV are located on the L gene communities in West Africa outside of its already [8,9]. Whatever the case, the ecological evidence is broad area of ruralendemicity. Indeed, urban clear; virulence for primates is a chance event, Lassa fever in West Africa has been occurring unrelated to the natural history of the virus.
with increasing frequency [15]. In early 2000, The distribution of Mastomys in West Africa is highly variable and in some areas, 50% of being seen in Nigeria, the most populous country domestic rodents may be Mastomys [4]. Since the in Africa (A Nasidi, personalcommunication).
rodents do not move far from their nest, and Since 1990, severe socialdisruption from conflicts because Lassa virus is transmitted vertically in and terror campaigns in Sierra Leone and Liberia rodents, infection in local populations of rodents have displaced up to 2 million people – 25% of tends to cluster. Thus, human infections tend also the population of the area – with a substantial to be focal with periodic familial or village clusters increase in the already large number of Lassa with secondary cases due to person-to-person spread. These outbreaks are seen against the Lassa fever is the exotic haemorrhagic fever background of primary infections from rodents most likely to occur in developed countries due to that make up the bulk of endemic disease.
infection in returning travellers. In the year 2000 at Infections peak between January and May – least four cases were imported into Europe [18].
during the dry season – but cases are seen year All died, due in great part to delay in diagnosis, round. Over 300 000 Lassa virus infections are estimated to occur annually, with several thou- therapy. Increased cases in non-West Africans in sand deaths [4,10–12]. Lassa fever occurs in all age 2000 have been seen as a result of United Nations groups and sexes, and not surprisingly given the (UN) peacekeeping efforts in Sierra Leone, where ubiquity of the rodent host, antibody prevalence the rebels’ stronghold is the centre of the Lassa increases with age. This is compatible with virus fever endemic area. One of the fatalcases in transmission to humans in and around the homes expatriates was an Englishman who had been where the Mastomys live. Estimates of antibody prevalence range from 4%–6% in Guinea to diamond mining area of eastern Sierra Leone [19].
15%–20% in Nigeria, though in some villages inSierra Leone as many as 60% of the population have evidence of past infection. Among hospita- Lassa fever begins insidiously, after an incubation lised patients, the mortality is 17% if untreated. In period of 7–18 days, with fever, weakness, endemic areas, Lassa fever may account for malaise, and severe headache – usually frontal, 10%–16% of all adult medical admissions and and a very painfulsore throat [20]. Up to a third of Copyright # 2001 John Wiley & Sons, Ltd.
Rev. Med. Virol. 2001; 11: 331–341.
hospitalised Lassa fever patients progress to a ambisense RNA of Mr 1.1–1.6r106, encodes the prostrating illness 6–8 days after onset of fever, glycoprotein precursor [GPC] and the nucleo- usually with persistent vomiting and diarrhoea.
protein (N). The genome is enclosed in a mem- Bleeding is seen in only 15%–20% of patients, brane bearing two glycosylated proteins of limited primarily to the mucosal surfaces or Mr 34 000–44 000 (G1) and 54 000–72 000 (G2), occasionally conjunctival haemorrhages or gastro- derived from GPC by post-translational cleavage.
intestinal or vaginal bleeding. Severe pulmonary Antigenic cross-reactivity by monoclonal anti- oedema and adult respiratory distress syndrome bodies has been detected at one epitopic site at is common in fatalcases with gross head and neck least across all known arenaviruses, but more cross reactivity occurs between more geographi- shock. Case fatality in hospitalised patients is cally proximal viruses [25]. Lassa, Junin and about 16%, higher in some Nigerian outbreaks Machupo viruses are categorised as Biosafety and in pregnant women in the third trimester Level4 (BSL4) laboratory agents, and require high considerably more (30%–70% depending on the containment facilities for cultivation or animal quality of obstetric care) [21]. Lassa fever has studies. LCMV and Mopeia are BSL3 agents.
considerable long-term sequelae, in that nearly30% of patients with Lassa fever infection suffer an acute loss of hearing in one or both ears [22].
Design of an effective vaccine requires some About half of these patients show a near or understanding of the immunology of the disease complete recovery by 3–4 months after onset, but against which the vaccine must protect. Clearly, the other half continue with significant sensori- this rodent virus is handled quite differently by neuraldeafness, which after about a year willbe the immune systems of rodents and primates. The immunological response in primates to arenavirus Though treatment with intravenous ribavirin infection is complex. In general, the evidence we has been shown to be effective, it is not widely have indicates that Lassa and LCM viruses available in the endemic areas [20]. Ribavirin must depend primarily on cytotoxic T-cell responses be administered in the first week of illness for for virus clearance, while neutralising antibodies optimalefficacy, and many patients often present are associated with clearance of viraemia due to to hospitallate in disease. Even in times of peace, the South American arenaviruses [26]. There uncounted numbers die without receiving medical appears to be a brisk B-cell response to Lassa care of any kind. Because of deteriorating social virus with a classic primary IgG and IgM antibody conditions due to armed conflict in eastern Sierra response early in the illness. Development of Leone and Liberia, where Lassa fever is highly antibody does not, however, coincide with virus prevalent, both the number of Lassa fever cases clearance, and high viraemia and high IgG and and mortality appear to have increased markedly.
IgM titres often coexist in both humans and In these circumstances, treatment can at best reach primates. Indeed virus may persist in the serum the fortunate few, and those may not always and urine of humans for severalweeks after infec- receive the drug sufficiently early to improve tion, and possibly in occult sites, such as renal outcome [17]. Even expatriates working in ende- tissue, for longer periods. Lassa virus specific mic areas appear to have died due to failure to cytotoxic T cell responses can be measured in institute prompt antiviraltherapy [18,19].
patients recovered from Lassa fever [27].
Neutralising antibodies to Lassa virus cannot be measured in the serum of patients at the begin- Like all arenaviruses, Lassa virus is an enveloped, ning of convalescence; in most people, and in pleomorphic, membrane virus with a mean dia- experimentally infected monkeys, they are never meter of 110–130 nm [3,23]. It contains two seg- detectable in a classical plaque-reduction neutra- ments of single-stranded RNA, tightly associated lisation assay. In a minority of patients some with a nucleocapsid protein of Mr 65 000–72 000.
low-titre serum neutralising activity may be 2.0–3.2r106, codes for the viralpolymerase and disease, but only using a fixed-serum, varying- a zinc binding RING protein [24]. The small virus dilution assay (log neutralisation assay) [28].
Copyright # 2001 John Wiley & Sons, Ltd.
Rev. Med. Virol. 2001; 11: 331–341.
Passive protection from Lassa virus has been employment, that is experience, actually has a demonstrated in animals given selected antiserum protective effect [32]. However simple this may but only at the time of or soon after inoculation seem, these practices are difficult to establish and with virus. While there have been anecdotal maintain on the scale needed in areas where training reports of the clinical effectiveness of Lassa is limited and basic hospital supplies not available.
immune plasma, controlled clinical trials with Lassa virus is acquired in the community either human convalescent plasma containing high- from infected rodents or from people. Rodent-to- titred antibodies have shown no protective effect.
human infection is highly associated with indis- Thus the clearance of Lassa virus appears to be criminate food storage, and practices such as independent of antibody formation, and presum- catching, cooking and eating rodents [4]. Person- ably depends on the CMI response. In Lassa fever to-person spread of Lassa virus in households is infections, the presence of antibody to neither common, and in villages, risk of infection is glycoprotein nor nucleoprotein at the time of associated with direct contact, nursing care or hospitaladmission is associated with survival, or sexualcontact with someone during the acute even attenuation of disease. Indeed there is some phases of illness. Preventing rodent/human con- correlation between death and early detection of tact will eliminate the bulk of the primary cases, and if these are prevented, then person-to-person These consistent observations contrast sharply spread will be eliminated also. Control could be with those made in Argentinian haemorrhagic achieved in good part by improving living fever (AHF), caused by the South American conditions, proper food storage and improve- arenavirus, Junin virus. Here neutralising anti- ments in education and generalhygiene in the bodies can be detected easily, and immune community, but in remote ruralAfrica this can be therapy has been shown to be very effective in difficult to achieve at the level of the general this disease, and to correlate with the level of population, and more difficult to sustain once the neutralising antibody. Nevertheless there is evi- threat of epidemics recede locally. Direct contact dence from vaccine studies in Argentina that between articles contaminated with virus and patients who do not produce measurable neutra- surfaces and cuts and scratches on bare hands lising antibodies following vaccination do mount and feet may be the most important and consistent a Junin-virus specific lymphocytic proliferative mode of transmission in endemic areas. The response [20]. The precise nature of protective sporadic pattern of human infection in the house- immune responses in arenaviruses, however, hold community excludes aerosol as a common remains to be elucidated using the more sophis- mode of transmission. Rodent controlcan reduce ticated assays now available, which for reasons of the risk of Lassa fever considerably, but rodent biosafety and inaccessibility of patients and speci- controlon the scale needed in ruralWest Africa is mens have not yet been applied to arenaviruses.
unlikely. Similarly the hoped for economicimprovements and consequent improvements in housing, food storage and education have not materialised, and are unlikely to do so soon in It has been shown clearly that infection of staff in conflict ravaged West Africa. On the contrary, hospitals in the endemic areas can be prevented Lassa fever cases continue to increase with displacement of large populations throughout (gloves, gowns, masks, prompt disinfection of the endemic areas in Liberia and Sierra Leone, contaminated equipment and spills [30,31]). This and in the socialchaos of politicaland religious is not expensive, but requires understanding of strife of Nigeria. The only rational near-term the risks and the discipline of good training and good clinical practice. If these rules are applied,hospitalpersonnelin endemic areas are at no greater risk of contracting Lassa fever in the Data from human observations in the field show hospitalthan in the community. Indeed Lassa that immunity is achievable since a single infec- infection in hospitalstaff is associated with tion with Lassa virus provides long-term protec- inexperience and poor education. Duration of tion against future disease. A second clinical Copyright # 2001 John Wiley & Sons, Ltd.
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attack of Lassa fever has never been documented ‘guilt by association’. In many ways it is an ideal despite more than 13 years of continuous observa- ‘natural’ vaccine, but both then and now concerns tion in a single endemic area (J.B. McCormick, for safety have hindered development and there unpublished data). People living or working in are currently no other candidates in sight [35,36].
conditions where repeated exposure could beexpected do have periodic rises in their Lassa virus specific antibody titre, but no disease.
A killed vaccine was tried in non-human primates Similarly, there is no evidence that persistence of and found to offer no protection at all [37].
virus in humans is ever a source of infection for (gamma irradiated) whole Lassa virus, resulted There is precedent for an arenavirus vaccine in in antibody responses to both proteins, and a brisk Argentina, where a successfulvaccine for AHF booster response following challenge, but all has now undergone Phase III studies. It is in use in animals died regardless, with serum virus titres the endemic area of Argentina, where it has all but equal to unvaccinated controls (Table 1). This eliminated the disease [33]. This is a live attenu- ated vaccine; designated Candid 1. This vaccine that protection would depend on the ability to was produced using the classical, but simple in vitro passage technology that has given ussome of our most successful vaccines; yellowfever, polio, measles. The vaccine has now been shown both to be safe in large-scale trials, and to have a protective efficacy of 84%. This introduc- The first genetically engineered vaccines appeared tion of a vaccine for an arenavirus is quite in the early 1980s. Clones containing sequences of remarkable, and gives hope that further vaccines, the smaller (S) segment of the Lassa virus genome particularly a vaccine for Lassa fever, may be were expressed as a fusion protein in Escherichia finally put in the field. Even though neutralising coli [38]. The Lister strain of vaccinia virus was antibodies are not found to be important in then used to construct a recombinant that expres- protection against Lassa virus challenge in mon- sed the nucleocapsid gene of Lassa virus. Guinea- keys, as they are with Junin virus, the ability to pigs immunised with the recombinant virus were protect monkeys by prior vaccination with Lassa protected against challenge of 102 of Lassa virus, glycoproteins makes it likely that a Lassa vaccine whereas controlanimals died [39]. This recombi- will be similarly successful, even though the nant, however, did not protect primates. It was Unfortunately the excellent molecular phylo- both guinea-pigs and primates were uniformly genetic analysis of the arenaviruses by Bowen et al.
[5] does not include the Candid 1, Junin vaccine Table 1. Virus titres following challenge in strain, and we have no information as to how this non-human primates vaccinated with killed live attenuated vaccine relates to the virulent Junin virus. This is information that might be helpful in the design of other arenavirus vaccinecandidates.
Studies of potentialvaccines to Lassa virus began in the 1980s. Soon after its isolation it was shown that Mopeia virus provides monkeys with full protection against fatal Lassa virus challenge [34].
However, data on Mopeia virus are limited, and the virus is classified as BSL3, mostly because of Copyright # 2001 John Wiley & Sons, Ltd.
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protected. All guinea-pigs vaccinated with the unvaccinated controls died after challenge with recombinant virus survived a lethal challenge Lassa virus. The two monkeys ‘vaccinated’ with infection with Lassa virus, whereas 80% of control Mopeia virus survived challenge with minimal animals died. The vaccinated guinea-pigs did, physicalor physiologicaldisturbances. However, however, develop transient, low-grade, fevers and both showed a transient, low-titre Lassa viraemia.
detectable viraemias following infection with All four animals vaccinated with V-LSGPC sur- Lassa virus, indicating that protection was not vived a challenge of 104 pfu of Lassa virus but complete [40]. Vaccine efficacy trials of vaccinia experienced a transient febrile illness and moder- vectored Lassa virus proteins further tested in ate physiological changes following challenge guinea-pigs indicated that both the nucleoprotein and the envelope glycoproteins are capable of A broader study of protection was performed eliciting a protective immune response against a using a range of recombinant vaccinia viruses lethal dose of Lassa virus. Ninety-four percent of expressing NP, GPC and combinations of these the guinea-pigs vaccinated with the nucleoprotein proteins [35]. The studies were performed using recombinant (V-LSN), 79% vaccinated with glyco- protein recombinant (V-LSGPC) and 58% vac- (rhesus) and 16 Macaca fascicularis (cynomolgus).
cinated with both recombinant viruses survived a The recombinant vaccinia viruses expressed Lassa virus challenge compared with only 14% S-segment Lassa structuralproteins derived from of unvaccinated animals and 39% of animals the Josiah strain of Lassa virus, namely (a) the full vaccinated with the unmodified strain of vaccinia.
length glycoprotein (V-LSG), (b) the nucleoprotein The protection resulting from vaccination with (V-LSN), (c) full length glycoprotein and nucleo- the recombinant virus vaccines did not correlate protein in the same construct (V-LSG/N) (d) and with the levels of prechallenge serum antibodies, single glycoproteins (V-LSG1, residues 1–296, and suggesting that a cell-mediated immune response V-LSG2, deletion of residues 67–234) [41,43]. Two is a criticalcomponent of protective immunity to animals were ‘vaccinated’ with Mopeia virus as a live attenuated positive control. All animals were The glycoprotein vaccine was tested in rhesus challenged subcutaneously with 103–104 pfu of monkeys using a closely related virus Mopeia the Josiah strain of Lassa virus. Following Lassa virus challenge all unvaccinated animals died (0% survival) (Table 2). Nine of ten animals Table 2. Vaccination and outcome in Lassa virus challenged non-human primates in astudy of monkeys vaccinated with vaccinia recombinants expressing Lassa glycoproteinsand/or nucleoprotein Copyright # 2001 John Wiley & Sons, Ltd.
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vaccinated with all proteins lived (90% survival).
to settle the issue of whether this protein used as Although no animals that received full-length a vaccine actually potentiates viraemia following glycoprotein alone had high-titre antibody prior challenge. These data show that the GPC gene is to challenge, 17/19 survived (88%). In contrast all necessary and sufficient to protect primates animals vaccinated with nucleoprotein developed against a large parenteral challenge dose. We high-titre antibody but 12/15 died (20% survival).
must conclude that antibody even to the Lassa All animals vaccinated with single glycoproteins, glycoprotein plays a minor, if any, role in G1 or G2 died, but all those that received both clearance of infection and protection in humans.
single glycoproteins (G1+G2) at separate sites In our studies, it was striking that high-titre survived, showing that both glycoproteins are immunofluorescent antibody to nucleoprotein in independently important in protection. Neither monkeys was totally unrelated to protection. This group of survivors had demonstrable antibody is consistent with the observations that high titre prior to challenge. Viraemias following challenge antibody early in disease may be detrimental in A trend towards increasing duration of challenge viraemia (days) was observed with increased interval between vaccination and challenge [35].
Amino acid sequence comparisons between the Improved survivalin three V-LSN vaccinated nucleoproteins and glycoproteins of the Josiah andNigerian strains of Lassa virus, the WE and ARM animals inadvertently challenged with a lower strains of LCMV, Tacaribe, and Pichinde viruses dose of Lassa virus suggest that both time and revealthat the externalG2 envelope glycoprotein challenge dose affect outcome. None of the is more conserved among different arenaviruses protective vaccines provided sterilising immu- than the internal nucleoprotein [44]. Monoclonal nity, since almost all surviving, asymptomatic antibody mapping of the glycoproteins of African animals experienced viraemia, even those vacci- arenaviruses also shows that the G2 is more nated with Mopeia virus, consistent with the conserved than G1. Indeed there is a conserved hypothesis that virus replication is controlled by B-cell epitope on G2 across all of the known CTL responses, and not antibody responses.
African arenaviruses including the protective There was some suggestion in this study that Mopeia virus, and most South American arena- those animals vaccinated with nucleoprotein viruses studied [25]. Given this information, alone fared badly, but a larger study is needed genetic diversity among Lassa viruses turns outto be greater than expected. On the basis of 54strains studied so far, there are four lineages, threefrom Nigeria and the fourth from Sierra Leone,Guinea and Liberia [5,6]. Overall strain variationin the NP gene is 27% at the nucleotide level, and15% at the amino acid level. This may not be of asmuch consequence to vaccine design as it firstappears because the variation at the level of theglycoprotein is much less, and we know that it isthe anti-glycoprotein CTL response that protects.
Variation between Mopeia and Lassa viruses inglycoprotein sequences ranges from 20% to 25%,nevertheless Mopeia protects non-human pri-mates against Lassa challenge [6,35]. Fortunatelyit may turn out the protective CTL epitopes arerelatively well conserved throughout the con-tinent. Since there is no evolutionary pressure on Figure 1. Viraemias in non-human primates following challenge the virus to evade the primate immune system, it with lethal Lassa virus. The V-LSN vaccinated animals thatsurvived were challenged with a lower titre of Lassa virus (103 vs is possible that a single vaccine strain will be adequate for the entire endemic region.
Copyright # 2001 John Wiley & Sons, Ltd.
Rev. Med. Virol. 2001; 11: 331–341.
virus DNA. This chimera might be a very inter- esting and very practicalmodelfor the future of Despite these encouraging results, the vaccinia vaccines, particularly for populations in develop- format is no longer tenable because of potential ing countries. Yellow fever chimera vaccines are side effects, particularly in Africa, where HIV already undergoing trials for Japanese Encephal- itis and Dengue, so the idea is not new. However, The population to be served is poor and the these last two diseases are caused by flaviviruses, virus is endemic in an area with poor or absent and the chimeras replace the yellow fever E infrastructure, so a Lassa virus vaccine must be proteins with the proteins of the related virus of cheap, easily and safely administered, and stable.
interest. A yellow fever/Lassa chimera requires a Since we have now clearly shown that a recombi- different approach – that of stable insertion of an nant vaccine bearing the glycoprotein affords protection, the first issue is the delivery formatfor this protein. There are severaloptions. Firstly anon-pathogenic vaccine such as Mopeia mightwork well, but safety concerns are likely to complicate its use. The attraction of the live attenuated vaccine is that a single shot, as with The population at risk encompasses most of the the 17D yellow fever vaccine, might well protect population of West Africa to Nigeria, of the order for life – or at least for a considerable number of of 200 million or more by the time we have a years – particularly for those living in endemic vaccine in place. The people most at risk are the areas and exposed to virus, who might therefore poorest of the ruralinhabitants and localhealth receive a silent, natural boost to immunity from care workers, who should be the first people time to time. Given the remoteness and mobility of offered the vaccine. Since the epidemiological the target population, this is a highly desirable profile of Lassa fever is similar to that for property for any vaccine candidate. However, live yellow fever, long-term objectives should envisage vaccines require a cold chain, and in the condi- inclusion of a Lassa vaccine in EPI for West Africa.
tions where the vaccine is most needed, this However, decisions such as these will depend largely on the format of the final vaccine, Killed vaccines have been shown to be quite particularly the recommended schedule for boo- ineffective, and are excluded from consideration.
Poxviruses, such as the Canarypox virus [45], (an In view of the high risk to hospitalstaff in avian virus which does not replicate in mam- endemic areas, all medical care personnel in the malian cells) is a possibility, but the question iswhether its immunogenicity will be sufficient, and endemic area should be offered the vaccine.
how many doses might be needed to achieve Recently aid workers, both UN personnel and protection. These recombinants are also very employees of non-governmental organizations have been infected in West Africa, and all A Lassa fever vaccine requires new approaches.
travellers to the region who expect to venture DNA vaccines would offer much in the way of outside the strict confines of the major cities and low cost, stable vaccines, but several booster doses the best hotels should be vaccinated. Finally, might be needed. Another approach is to use the laboratory staff in any country likely to receive 17D strain of yellow fever virus as a vehicle, specimens from Lassa virus infected patients, staff preferably without losing yellow fever anti- caring for sick returning travellers from Lassa genicity, since the population at risk for Lassa endemic regions, or those working with Lassa fever, is also exposed to yellow fever [46]. For the virus in a research capacity, would also benefit long term, a yellow fever/Lassa fever chimera from the vaccine. Indeed the existence of the vaccine for use in EPI in West Africa is a very vaccine should allow the virus to be downgraded attractive solution, however, this would require a to BSL3, since at that point it would not only be cold chain. The cDNA clone of yellow fever could treatable but vaccine preventable. This would give also be used as a vehicle for delivery of Lassa enormous impetus to future research.
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the 1940s. These epidemics are the consequence of failure of political will to implement those The economic and political obstacles to producing vaccines that already exist [47]. This can be an effective Lassa fever vaccine far outweigh the blamed on inertia, disinterest, corruption, civil practicaland scientific problems. In the past two strife; but the fact remains that the people needing decades no vaccine destined primarily for popula- the vaccines do not receive them, and for the most tions in developing countries has been developed part the global institutions such as the World and marketed. The exception is the Candid 1 Health Organization or the UN seem relatively vaccine for AHF, but it must be remembered that this vaccine was developed and tested by the There is some hope. Poor populations may lack United States Army, whose priorities are rightly education, but they are not unintelligent, and not protection of military personnel. Even this vaccine devoid of resources. Even the poorest will find a is somewhat of a fortunate aberration since the few pence for the welfare of his or her family if he strategic importance of AHF is unclear. The fear or she perceives the danger and appreciates the of biological warfare, and manipulation of the benefit of the commodity offered. Free vaccines haemorrhagic fever viruses, including Lassa virus, and medications often become devalued in the to produce weapons has spurred some publicly eyes of the recipient who has made no investment, funded research. The fact remains, however, however small, and who may not wholly under- that pharmaceuticalcompanies, understandabl stand or trust the motives of outsiders who come answerable to their shareholders, do not and will to give them. If the system is unreliable and not consider a Lassa fever vaccine as a marketable corrupt the mistrust is exacerbated. An effort to vaccine. Public and private funding agencies may market vaccines at a low price and to educate the support some research, but not at the levels population at the same time about the benefits is needed to produce a human use vaccine for an ‘orphan’ disease. The costs and complexity of Among the viralhaemorrhagic fevers, Lassa conducting clinical trials continue to spiral out of fever along with Hantaviruses afflicts the greatest sight. The ethicalissues surrounding HIV vaccines number of victims, and presents us with the and their testing in the field are becoming realface of an emerging disease that coul increasingly contentious, and adding considerably threaten larger communities. We have shown to costs of trials. The truth today is that vaccines that an effective and safe vaccine can be made are developed for the wealthy countries where and could be avidly pursued. The challenge to us return on investment can be accurately predicted, now is to overcome the political and economic and their cost is rising dramatically. At the same obstacles, and put this much-needed vaccine in time the poorer countries that need the vaccines are becoming relatively poorer, and the hope ofvaccines tailored for their needs diminishes.
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