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[(Morrill)-417.9(et)-418.2(al.)-415.9(2013\),)-417.9(and)-419.2(inactivated)-420.5(whole)-416.6(virus)-420.1(vaccines)]TJ
T*
[(\(Pittman)-316.7(et)-320.3(al.)-317.9(2000\).)-314.2(Although)-315.2(subunit)-318.8(vaccines)-324.4(for)-314.3(RVFV)]TJ
T*
[(are)-201.4(generally)-203.7(considered)-198.7(safe,)-205.8(and)-200.3(recently)-202.6(some)-196.7(progress)-205.4(has)]TJ
0 -1.1174 TD
[(been)-358.1(made)-359.3(in)-359.4(their)-364(development,)-360.4(evaluation)-360.5(of)-359.3(immunoge-)]TJ
0 -1.1116 TD
[(nicity)-428.6(and/or)-422.6(efcacy)-432.6(in)-428.5(a)-422.7(target)-429.6(species,)-429.1(sheep,)-431.5(has)-424.7(been)]TJ
T*
[(performed)-335.9(for)-337.3(a)-336.3(few)-339.4(candidates)-338.3(\(Kortekaas)-343.6(et)-337.6(al.)-335.2(2012,)-336.1(Or-)]TJ
0 -1.1174 TD
[(eshkova)-332.4(et)-331.8(al.)-335.2(2013\).)-331.5(On)-337.1(the)-332.9(other)-329.3(hand,)-337.3(production)-334.9(of)-330.5(live)]TJ
0 -1.1116 TD
[(vaccines)-428.1(requires)-425.7(high)-425(level)-422.8(of)-428.4(biosafety,)-424.6(and)-424.9(their)-421.6(use)-430.5(is)]TJ
T*
[(associated)-343.8(with)-345.4(potential)-341.1(risk)-344.1(to)-342.1(personnel)-340.5(and)-344.3(reversion)-346.2(to)]TJ
0 -1.1174 TD
[(virulence)-359.2(in)-353.7(vaccinated)-356.9(hosts.)-354.3(Therefore,)-357.8(the)-355.9(general)-356.9(avail-)]TJ
0 -1.1116 TD
[(ability)-308.9(of)-313.2(a)-307.5(safe,)-315.2(efcacious)-314.9(vaccine)-312(with)-310.8(DIVA)-312.3(\(differenti-)]TJ
T*
[(ating)-208.5(infected)-214.1(from)-207.2(vaccinated)-212.9(animals\))-214(compatibility)-208.7(will)-213(be)]TJ
0 -1.1174 TD
[(extremely)-441.1(valuable)-444.5(to)-445.8(endemic)-438.8(and)-442.2(nonendemic)-447.9(countries)]TJ
0 -1.1116 TD
[(outside)-279.6(Africa.)]TJ
1.0137 -1.1116 TD
[(In)-422.6(this)-430.7(study,)-423.6(we)-430.5(describe)-432.7(the)-425(expression)-433.5(of)-428.4(the)-425.1(RVFV)]TJ
-1.0137 -1.1116 TD
[(structural)-353.3(glycoproteins)-350.9(Gn)-354.4(and)-350(Gc)-349.8(and)-355.8(assess)-353.7(their)-346.7(immu-)]TJ
0 -1.1174 TD
[(nogenicity)-486(in)-486.1(a)-486.1(natural)-488.3(target)-487.2(species,)-492.4(sheep.)-489.1(The)-483.7(results)]TJ
0 -1.1116 TD
[(demonstrate)-316.4(the)-315.6(induction)-311(of)-313.2(a)-313.3(strong)-311.8(virus)-316.4(neutralizing)-316.7(an-)]TJ
T*
[(tibody)-490.7(response)-488.8(with)-495.1(potentially)-487.4(protective)-498.7(titers)-491.7(induced)]TJ
0 -1.1174 TD
[(within)-416.8(2)-415.8(weeks)-417.4(after)-422.6(the)-419.3(primary)-419.1(vaccination)-420.3(without)-417.9(any)]TJ
0 -1.1116 TD
[(noticeable)-453.8(adverse)-460.2(reactions.)-454.6(Taken)-458.3(together,)-452.5(the)-453.8(ndings)]TJ
T*
[(suggest)-527(that)-535.7(a)-526.4(baculovirus-expressed)-535.4(RVFV)-531.2(glycoprotein)]TJ
0 -1.1174 TD
[(subunit)-457(vaccine)-456(could)-461.8(be)-452.6(a)-457.3(potential)-456.3(viable)-458.5(candidate)-464.1(for)]TJ
0 -1.1116 TD
[(development)-282.1(of)-284.4(an)-279.8(effective)-285.5(vaccine)-283.2(against)-280.8(RVFV.)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 310.8472 314.192 Tm
[(Materials)-332.7(and)-331.9(Methods)]TJ
/F10 1 Tf
0 -1.8336 TD
[(Cell)-336.3(cultures)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 281.3102 Tm
[(T)15(h)0(e)-251(A)15.3(fr)20.9(ic)25.3(an)-251(gr)20.9(e)15(e)0(n)-251(m)15(on)20.8(ke)25.4(y)-260.3(c)0(e)18.5(l)16.1(ls)20.9(,)-256.9(V)0(e)18.8(r)0(o)-244.1(E)0(6)-251.1(\()0(A)25.8(m)0(e)18.4(r)16.2(ic)19.6(an)-245.3(Ty)19.6(pe)]TJ
-1.0137 -1.1116 TD
[(C)15.2(u)0(l)20.7(t)0(u)26.5(r)0(e)-233.7(C)0(o)19.8(l)0(l)26.3(e)0(c)18.5(t)16.1(io)20.7(n)-243([)0(A)20(T)15(CC)18.8(])16.2(,)-245.3(Ma)24.5(na)19.7(ss)21.2(a)15(s)0(,)-234.7(V)0(A)24.9(\))0(,)-234.9(w)15.3(er)19.7(e)-244.2(m)0(a)24.2(i)0(n)20.7(t)0(a)25.3(i)0(n)20.7(e)15(d)]TJ
0 -1.1174 TD
[(in)-255.8(E)15(a)0(g)19.7(l)16.1(e)19.7(s)-265.8(m)0(i)19.5(n)16.2(im)19.5(a)15(l)-266.2(es)19.9(se)19.9(n)16.2(t)0(i)20.6(a)15(l)-271.9(m)15(ed)19.7(i)16.1(u)0(m)-256.9(\()0(C)19.8(o)16.2(rn)20.9(in)26.5(g)-266(C)0(e)18.6(l)0(l)26.3(g)0(r)20.9(o)0(,)-252.2(M)0(a)18.8(n)16.2(-)]TJ
0 -1.1116 TD
[(a)15(s)0(s)21.2(a)0(s)19.9(,)-233.8(V)15.3(A)0(\))-221.9(s)0(u)21(p)0(p)26.6(l)0(e)19.6(m)15(en)19.7(te)25.3(d)-237.2(w)15.3(it)20.6(h)-231.5(1)0(0)20.8(%)-232.5(f)16.2(e)0(t)19.6(a)0(l)-222.4(b)0(o)26.6(v)0(i)20.7(n)0(e)-222.2(s)0(e)25.6(r)0(u)20.9(m)-232.7(\(F)21(B)15.2(S)0(\))21(,)]TJ
/F7 1 Tf
T*
(l)Tj
/F4 1 Tf
.4896 0 TD
[(-)16.2(g)0(l)20.7(u)0(t)26.5(a)0(m)18.4(i)16.1(ne)19.7(,)-757.9(a)15(nd)-751(p)16.2(e)0(n)19.7(i)16.1(ci)19.5(ll)26.3(in)20.7(-s)21.1(t)16(r)0(e)19.7(p)0(t)26.5(o)0(m)19.6(y)16.2(ci)19.5(n)-755.6(\()0(I)20.9(n)0(v)26.6(i)0(t)20.6(r)0(o)26.6(g)0(e)19.7(n)0()26.6(L)0(i)19.5(f)16.2(e)]TJ
-.4896 -1.1174 TD
[(T)15(e)0(c)18.5(h)0(n)26.6(o)0(l)20.7(o)0(g)26.6(i)0(e)19.6(s)0(,)-355.7(C)0(a)18.6(r)16.2(ls)20.9(ba)19.7(d)16.2(,)-372(CA)24.7(\).)-361.6(Th)25.4(e)-370.9(c)0(u)19.7(l)0(t)26.3(u)0(r)20.9(e)0(s)-360.3(w)15.3(er)19.7(e)-370.9(m)0(a)24.2(i)0(n)20.7(t)0(a)25.3(i)0(n)20.7(e)15(d)]TJ
0 -1.1116 TD
-.015 Tc
[(at)-350.3(3)-15(7)]TJ
/F8 1 Tf
2.0274 0 TD
0 Tc
()Tj
/F4 1 Tf
.3801 0 TD
[(C)-336.2(i)0(n)-324.9(h)16.2(um)19.6(i)16(d)0(i)20.7()0(e)25.6(d)-335.2(5%)-320(CO)]TJ
7.3823 0 0 6.5614 430.0723 213.9023 Tm
(2)Tj
9.843 0 0 9.843 437.0455 215.5464 Tm
[(at)25.3(mo)19.6(sp)26.8(he)19.7(re)25.5(.)-337.5(T)15(he)]TJ
/F9 1 Tf
6.9635 0 TD
-.0192 Tc
[(Sp)-19.2(od)-19.2(o)7.4(p)-19.2(te)-19.2(r)6.4(a)]TJ
-19.7846 -1.1116 TD
0 Tc
[(fr)26.7(ug)20.8(ip)26.5(er)19.9(da)]TJ
/F4 1 Tf
4.6308 0 TD
[(\(S)21(f9)26.6(\))-461.8(c)0(e)18.5(l)16(ls)-451.4(\(I)26.7(nv)20.8(it)26.3(ro)20.9(ge)25.4(n)20.8(Li)25.3(fe)-452.6(T)15(e)0(c)18.5(h)0(n)26.6(o)0(l)20.7(o)0(g)26.6(i)0(e)19.6(s)0(\))-445.5(w)0(e)18.8(r)16.2(e)]TJ
-4.6308 -1.1174 TD
[(m)15(a)0(i)19.5(n)0(t)26.5(a)0(i)19.5(n)0(e)25.4(d)-358.2(i)16.1(n)-358.2(S)16.3(F)0(M)-342.8(9)0(0)20.8(0)-352.4(II)-342(me)18.4(d)16.2(i)0(u)20.7(m)-353.7(su)21(p)16.2(p)0(l)20.7(e)0(m)24.2(e)0(n)19.7(t)16.1(ed)-343.2(wi)19.8(th)-342.2(10)20.8(%)]TJ
0 -1.1116 TD
[(FB)25.7(S)-369.6(a)0(n)25.4(d)-369.7(pe)25.4(ni)20.7(ci)25.3(ll)20.6(in)26.5(-s)21.1(tr)20.7(e)15(p)0(t)20.7(o)16.2(my)19.6(c)15(i)0(n)-359.4(\()0(I)26.7(n)0(v)20.8(i)0(t)26.3(r)0(o)20.9(g)0(e)25.4(n)0()20.8(L)0(i)25.3(f)0(e)-360.4(T)15(ec)18.5(h)16.2(n)0(o)20.8(l)0(o)26.5(-)]TJ
T*
[(gi)26.5(es)19.9(\).)-257.9(T)15(h)0(e)19.7(s)16.4(e)-273(c)0(e)24.3(l)0(l)20.6(s)-265.8(we)18.8(r)16.2(e)-273(m)15(a)0(i)19.5(n)16.2(ta)19.6(in)26.5(ed)-262.5(a)15(t)-271.9(2)16.2(7)]TJ
/F8 1 Tf
15.8565 0 TD
()Tj
/F4 1 Tf
.3859 0 TD
-.0152 Tc
(C.)Tj
/F10 1 Tf
8.9663 0 0 8.9663 310.8472 149.7826 Tm
0 Tc
[(Construction)-333.6(of)-330.4(recombinant)-340.1(bacmid)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 133.3417 Tm
[(The)-322.4(cloning)-320.2(and)-327(construction)-326.7(of)-318.9(the)-327.1(recombinant)-328.1(bacmid)]TJ
-1.0137 -1.1116 TD
[(was)-206.7(carried)-207.1(out)-210.8(as)-204.8(described)-209.1(previously)-208(\(Faburay)-212.5(et)-205.1(al.)-208.5(2013\).)]TJ
T*
[(Briey,)-190.7(the)-188.9(coding)-186.5(sequences)-192.7(of)-186.5(the)-188.9(RVFV)-191.3(structural)-192(proteins)]TJ
0 -1.1174 TD
[(Gn)-406.3(and)-401.9(Gc)-407.4(were)-410.8(retrieved)-405.3(from)-408.7(the)-407.8(RVFV)-404.4(ZH548)-405(isolat)-8(e)]TJ
0 -1.1116 TD
[(sequences)-313.7(\(GenBank)-306.8(acces)-10(sion)-303.8(no.)-310.9(DQ380151\),)-308.8(and)-309.7(the)-309.9(se-)]TJ
T*
[(quences)-229.9(were)-232.2(synthesized)-228.6(\(GENEWIZ,)-232.9(Inc.,)-230.2(San)-228.9(Diego,)-230(CA\))]TJ
0 -1.1174 TD
[(with)-420.2(molecular)-418(modications.)-423.4(For)-417.8(Gn,)-421.2(the)-419.3(transmembrane)]TJ
0 -1.1116 TD
[(domain)-366.2(and)-367.3(cytoplasmic)-368.4(tail)-368.8(were)-370.4(deleted)-368.6(from)-362.7(the)-367.5(coding)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 59.7543 749.7069 Tm
[(SUBUNIT)-340.8(VACCINE)-333.1(AGAINST)-341(RIFT)-333.8(VALEY)-337.3(FEVER)-331(VIRUS)-25644.4(747)]TJ
ET
endstream
endobj
73 0 obj
<>stream
/GS1 gs
BT
/F4 1 Tf
9.843 0 0 9.843 62.022 221.0456 Tm
0 0 0 1 k
0 Tc
0 Tw
[(sequence)-335.8(and)-332.8(designated)-337.1(as)-331.5(the)-332.9(Gn)-331.4(ectod)-8(omain)-330.6(\(Gne\))-335.8(\(Fig.)]TJ
0 -1.1116 TD
[(1A\).)-387.7(To)-389.3(ensure)-394.6(translocation)-392.5(of)-388.1(both)-390.4(Gne)-391.2(and)-384.6(Gc)-390.1(into)-390.6(the)]TJ
0 -1.1174 TD
[(endoplasmic)-564.1(reticulum)-561(\(ER\))-553.7(and)-563.2(processing)-560.2(through)-555(the)]TJ
0 -1.1116 TD
[(cellular)-283.4(glycosylation)-287.7(pathway,)-285.2(a)-278.7(specic)-287.4(54-nucleotide)-283.1(sig-)]TJ
T*
[(nal)-344.4(peptide)-344.4(\(SP\))-338.1(sequence)-347.3(was)-345(identied)-340.8(in)-342.1(the)-344.4(M)-341.8(segment)]TJ
0 -1.1174 TD
[(of)-520.5(the)-517.2(RVFV)-519.6(genome,)-520.5(as)-515.8(described)-525.9(previously)-519.1(\(Faburay)]TJ
0 -1.1116 TD
[(et)-406.7(al.)-398.6(2013\))-408.7(\(sequences)-406.9(are)-403(available)-406.6(on)-405.4(request\).)-406.1(This)-403(SP)]TJ
T*
[(sequence)-197.6(was)-189.5(fused)-190.8(to)-192.4(the)-188.9(5)]TJ
/F8 1 Tf
10.857 0 TD
()Tj
/F4 1 Tf
.4377 0 TD
[(end)-194.5(of)-186.5(the)-194.7(Gne)-189.6(and)-194.5(Gc)-188.5(sequences)]TJ
-11.2948 -1.1174 TD
[(\(Fig.)-307.3(1B\).)-301.5(The)-305.2(signal)-307.3(peptide)-309.8(contained)-307.4(a)-301.8(cleavage)-314.3(site,)-302.8(and)]TJ
0 -1.1116 TD
[(cleavage)-481.3(is)-480.2(catalyzed)-476.8(by)-480.3(signal)-474.4(peptidases)-480.9(located)-483.8(in)-474.6(the)]TJ
T*
[(lumen)-468.8(of)-462.9(the)-465.4(ER,)-462.9(a)-468.8(site)-466.4(for)-464(protein)-464.1(translation)-469.8(and)-465.2(post-)]TJ
T*
[(translational)-288.9(modication.)]TJ
1.0137 -1.1174 TD
[(The)-264.8(nucleoprotein)-271.6(\(N\))-269.1(nucleotide)-274.1(sequence)-266.7(was)-270.1(amplied)]TJ
-1.0137 -1.1116 TD
[(by)-232.6(PCR)-241.4(from)-236(the)-235(pET30)-232.5(Ek/LIC)-240.5(recombinant)-235.9(plasmid)-240.6(\(a)-233.7(gift)]TJ
T*
[(from)-454.8(Dr.)-455.7(Friedeman)-458.1(Weber,)-457(University)-456.7(of)-451.4(Marburg,)-456.6(Ger-)]TJ
0 -1.1174 TD
[(many\),)-414.5(which)-410.9(contained)-416.8(the)-407.8(entire)-418.1(coding)-411.1(region)-411(of)-411.1(the)-413.5(S)]TJ
25.504 16.7032 TD
[(segment)-477.7(of)-468.7(the)-476.9(RVFV)-473.6(strain)-474.3(ZH548.)-471.8(The)-472.2(RVFV-specic)]TJ
0 -1.1116 TD
[(sequences)-480.7(were)-479.9(cloned)-481.4(into)-471.2(a)-480.3(pFastBac/CT-TOPO)-482.1(vector)]TJ
0 -1.1174 TD
[(\(Invitrogen)-8.8(Life)-519.5(Technologi)-9(es\))-522.6(in-frame)-525(with)-523.9(a)-520.6(carboxy-)]TJ
0 -1.1116 TD
[(terminal)-295(polyhistidine-tagged)-296.8(protein,)-289(resulting)-293.5(in)-290.3(the)-292.6(donor)]TJ
T*
[(plasm)-7.8(ids)-527.4(pRF-Gne,)-538.2(pRF-Gc,)-531.3(and)-534.4(pRF-N.)-529(The)-535.6(individual)]TJ
0 -1.1174 TD
[(donor)-604.5(plasmids)-598.6(were)-600.8(transformed)-603(into)-597.9(MAX)-605(Efciency)]TJ
0 -1.1116 TD
[(DH10B)-8.3(ac-competent)]TJ
/F9 1 Tf
8.9333 0 TD
[(E.)-408.9(coli)]TJ
/F4 1 Tf
3.1966 0 TD
[(to)-405.5(generate)-416.7(recombinant)-414.5(bac-)]TJ
-12.1299 -1.1116 TD
[(mids.)-556.2(Recombina)-10(nt)-549.5(bacm)-7.9(ids)-550.4(were)-560.5(puried)-556(and)-557.4(used)-552.5(for)]TJ
0 -1.1174 TD
[(transfection)-287.5(to)-278.8(express)-286.1(the)-281.1(respective)-286.4(proteins.)]TJ
/F10 1 Tf
8.9663 0 0 8.9663 313.0582 105.959 Tm
[(Recombinant)-340.8(baculovirus)-332.9(expression)-335.9(and)-329.4(purication)]TJ
0 -1.2203 TD
[(of)-336.7(RVFV)-333.1(proteins)]TJ
/F4 1 Tf
9.843 0 0 9.843 323.0361 78.5763 Tm
[(Recombinant)-571.1(baculovirus)-573.2(expression)-566(of)-566.6(the)-569(respective)]TJ
-1.0137 -1.1116 TD
[(RVFV)-560(proteins)-557.2(was)-552.3(carried)-558.4(out)-550.6(as)-556.1(described)-560.5(previously)]TJ
0 -1.1174 TD
[(\(Fabur)-7.5(ay)-268.3(et)-268.4(al.)-266.1(2013\).)-268.1(Briey,)-271.4(puried)-268(recombinant)-270.5(bacmids)]TJ
ET
q
1 i
138.841 732.245 m
475.37 732.245 l
475.37 329.896 l
138.841 329.896 l
W n
q
336.928 0 0 402.35 138.841 329.896 cm
/Im1 Do
Q
Q
BT
/F6 1 Tf
9.845 0 0 9.845 62.022 313.1149 Tm
[(FIG.)-359.8(1.)]TJ
/F4 1 Tf
4.1404 0 TD
[(Creation)-357.1(of)-359(amino-terminus)-364.4(glycoprotein)-360.3(ectodomain)-360.4(\(Gne\))-358.2(and)-361.2(carboxyl-terminus)-361.6(glycoprotein)-360.3(\(Gc\))-363(recombi-)]TJ
-4.1404 -1.0135 TD
[(nant)-385.4(constructs)-392.3(and)-384.2(recombinant)-390.2(protein)-382.8(expression.)-389.7(\()]TJ
/F6 1 Tf
22.2798 0 TD
(A)Tj
/F4 1 Tf
.7198 0 TD
[(\))-386.8(Diagrammatic)-388.8(representation)-393.2(of)-382(deletion)-390.9(of)-382(the)-390.1(transmembrane)]TJ
-22.9996 -1.0135 TD
[(\(TM\))-299.6(domain)-296.4(\(black)-302.1(boxes\))-300.6(and)-297.8(the)-298(cytoplasmic)-298.1(tail)-299.3(of)-301.4(Gn.)-294.1(\()]TJ
/F6 1 Tf
24.7848 0 TD
(B)Tj
/F4 1 Tf
.668 0 TD
[(\))-294.7(Diagrammatic)-308.2(representation)-301.1(of)-295.7(signal)-301(peptide)-297.6(\(SP\))-297.3(with)-298.8(a)]TJ
-25.4528 -1.0077 TD
[(signal)-277.9(peptidase)-271.7(cleavage)-278.8(site)-276(\(scissors\))-275.5(identied)-276.5(in)-272.8(the)-275(M)-272.5(segment)-275.3(of)-272.6(the)-275(Rift)-276(Valley)-274.4(fever)-272.2(virus)-275.6(\(RVFV\))-279.1(genome)-274.3(is)-272.6(fused)]TJ
0 -1.0135 TD
[(to)-295.8(the)-298(5)]TJ
/F8 1 Tf
3.0981 0 TD
()Tj
/F4 1 Tf
.5471 0 TD
[(terminus)-298.4(of)-295.7(Gne)-292.9(and)-297.8(Gc.)-295.3(\()]TJ
/F11 1 Tf
10.6821 0 TD
(c)Tj
/F4 1 Tf
.501 0 TD
[(\))-294.7(Putative)-298.5(glycosylation)-297.9(sites)-294.1(\(Gerrard)-299(and)-292.1(Nichol)-302(2007\).)-290.5(\()]TJ
/F6 1 Tf
23.7079 0 TD
(C)Tj
/F4 1 Tf
.7198 0 TD
[(\))-294.7(Coomassie)-301.2(Blue)-294.2(stain)-294.2(of)]TJ
-39.256 -1.0135 TD
[(puried)-417(recombinant)-419(Gne,)-423(Gc,)-416.2(and)-418.8(empty)-416.3(baculovirus-infected,)-421.1(mock-puried)-418.5(cell)-421.3(lysate)-417.3(\(EBM\).)-420.2(M,)-419.8(molecular)-417(weight)]TJ
T*
(marker.)Tj
/F3 1 Tf
8.9663 0 0 8.9663 62.022 749.6502 Tm
(748)Tj
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