%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Timothy Lahey, Dominick Laddy, Krystal Hill, Jacqueline Schaeffer, Alison Hogg, James Keeble, Belinda Dagg, Mei Mei Ho, Robert D. Arbeit, C. Fordham von Reyn
Immunogenicity and Protective Efficacy of the DAR-901 Booster Vaccine in a Murine Model of Tuberculosis
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 14 0 R/Contents 15 0 R/TrimBox[0 0 612 792]>>
endobj
14 0 obj
[16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R]
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref001)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref002)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref003)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref004)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref005)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref006)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref007)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref008)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref010)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.ref011)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168521.g001)>>
endobj
15 0 obj
[27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R 39 0 R 40 0 R 41 0 R]
endobj
27 0 obj
<>stream
q
0.45 0.36 0.35 0.01 k
0 w
575.9997 661.9102 m
199.9998 661.9102 l
199.9998 662.4102 l
575.9997 662.4102 l
f*
0.83 0.64 0.02 0 k
559.6157 602.1921 m
564.378 602.1921 l
h
f*
200.0126 589.2094 m
204.7748 589.2094 l
h
f*
306.1417 563.1874 m
310.9039 563.1874 l
h
f*
203.4142 550.2047 m
208.1764 550.2047 l
h
f*
212.5417 550.2047 m
217.3039 550.2047 l
h
f*
236.126 537.222 m
240.8882 537.222 l
h
f*
203.4142 511.2 m
208.1764 511.2 l
h
f*
551.2819 472.1953 m
556.0441 472.1953 l
h
f*
200.0126 459.2126 m
209.537 459.2126 l
h
f*
291.9685 433.1906 m
301.4929 433.1906 l
h
f*
200.0126 348.548 m
219.5717 348.548 l
h
f*
0 g
1 j
1 J
11.4998 0 0 11.4998 200.0125 706.3937 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Conclusions)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 689.3858 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(DAR-901)Tj
4.2907 0 Td
(induces)Tj
3.6224 0 Td
(cellular)Tj
3.3359 0 Td
(and)Tj
1.8679 0 Td
(humoral)Tj
3.7894 0 Td
(immunity)Tj
4.1833 0 Td
(and)Tj
1.862 0 Td
(boosts)Tj
3.1389 0 Td
(protection)Tj
4.5593 0 Td
(from)Tj
/F7 1 Tf
2.2081 0 Td
(M)Tj
/F0 1 Tf
(.)Tj
/F7 1 Tf
1.3248 0 Td
(tuberculosis)Tj
/F0 1 Tf
-34.1827 -1.474 Td
(compared)Tj
4.6189 0 Td
(to)Tj
1.0444 0 Td
(a)Tj
0.7698 0 Td
(homologous)Tj
5.6036 0 Td
(BCG)Tj
2.3751 0 Td
(boost.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 620.2771 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 603.2692 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Tuberculosis)Tj
5.3517 0 Td
(sickens)Tj
3.1011 0 Td
(over)Tj
1.9786 0 Td
(eight)Tj
2.1997 0 Td
(million)Tj
3.1237 0 Td
(people)Tj
2.8516 0 Td
(and)Tj
1.7348 0 Td
(kills)Tj
1.8369 0 Td
(more)Tj
2.3414 0 Td
(than)Tj
2.0239 0 Td
(one)Tj
1.7008 0 Td
(million)Tj
3.1237 0 Td
(every)Tj
2.3471 0 Td
(year)Tj
1.9049 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
-35.6199 -1.2982 Td
(2)Tj
0 g
(].)Tj
1.2585 0 Td
(The)Tj
1.7858 0 Td
(standard)Tj
3.7191 0 Td
(vaccine)Tj
3.1974 0 Td
(against)Tj
3.0274 0 Td
(tuberculosis,)Tj
/F12 1 Tf
5.2668 0 Td
[()47()3()7()13()4()6()-4()11()2( )-9(\n)12()12()]TJ
6.3212 0 Td
[()4()12(\r)-13(\n)-4()]TJ
/F8 1 Tf
(,)Tj
2.4151 0 Td
(bacille)Tj
2.7666 0 Td
(Calmette-Guerin)Tj
-29.7579 -1.3039 Td
(\(BCG\),)Tj
3.084 0 Td
(is)Tj
0.8447 0 Td
(effective)Tj
3.515 0 Td
(when)Tj
2.4037 0 Td
(administered)Tj
5.4879 0 Td
(to)Tj
1.0261 0 Td
(mycobacteria-na)Tj
/F13 1 Tf
[()]TJ
/F8 1 Tf
(ve)Tj
8.0504 0 Td
(infants,)Tj
3.1918 0 Td
(but)Tj
1.5533 0 Td
(protection)Tj
4.3824 0 Td
(appears)Tj
-33.5393 -1.2983 Td
(to)Tj
1.0261 0 Td
(wane)Tj
2.3074 0 Td
(after)Tj
2.0352 0 Td
(1015)Tj
2.6419 0 Td
(years)Tj
2.262 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(])Tj
1.3777 0 Td
(and)Tj
1.7291 0 Td
(boosting)Tj
3.6793 0 Td
(with)Tj
2.0013 0 Td
(another)Tj
3.3278 0 Td
(administration)Tj
6.1682 0 Td
(of)Tj
1.0148 0 Td
(BCG)Tj
2.1827 0 Td
(is)Tj
0.8447 0 Td
(ineffective)Tj
-32.5982 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2529 0 Td
(5)Tj
0 g
(])Tj
1.0261 0 Td
(The)Tj
1.7745 0 Td
(development)Tj
5.4028 0 Td
(of)Tj
1.0091 0 Td
(improved)Tj
4.0989 0 Td
(vaccines)Tj
3.5489 0 Td
(against)Tj
3.0161 0 Td
(tuberculosis)Tj
5.0343 0 Td
(is)Tj
0.839 0 Td
(thus)Tj
1.9276 0 Td
(a)Tj
0.6463 0 Td
(critical)Tj
2.9423 0 Td
(global)Tj
2.6192 0 Td
(health)Tj
-35.138 -1.2982 Td
(priority)Tj
3.2711 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(].)Tj
1.6044 0 Td
(Modeling)Tj
4.0989 0 Td
(studies)Tj
2.982 0 Td
(indicate)Tj
3.4129 0 Td
(that)Tj
1.7745 0 Td
(an)Tj
1.2075 0 Td
(effective)Tj
3.5093 0 Td
(BCG)Tj
2.177 0 Td
(booster)Tj
3.1975 0 Td
(for)Tj
1.3833 0 Td
(adolescents)Tj
4.7735 0 Td
(and)Tj
1.7291 0 Td
(adults)Tj
-35.121 -1.3039 Td
(will)Tj
1.661 0 Td
(have)Tj
2.0637 0 Td
(a)Tj
0.6519 0 Td
(greater)Tj
3.0047 0 Td
(impact)Tj
2.982 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4684 0 Td
(global)Tj
2.6248 0 Td
(pandemic)Tj
4.1839 0 Td
(than)Tj
2.0296 0 Td
(an)Tj
1.2019 0 Td
(improved)Tj
4.1046 0 Td
(BCG)Tj
2.1826 0 Td
(for)Tj
1.3833 0 Td
(priming)Tj
3.4753 0 Td
(infants)Tj
-34.2933 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(].)Tj
1.1962 -1.2983 Td
(Our)Tj
1.8651 0 Td
(work)Tj
2.2791 0 Td
(has)Tj
1.542 0 Td
(focused)Tj
3.2825 0 Td
(on)Tj
1.2756 0 Td
(development)Tj
5.4085 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(booster)Tj
3.1918 0 Td
(vaccine)Tj
3.1975 0 Td
(for)Tj
1.3833 0 Td
(BCG.)Tj
2.4038 0 Td
(We)Tj
1.61 0 Td
(have)Tj
2.058 0 Td
(shown)Tj
2.8516 0 Td
(previ-)Tj
-35.2117 -1.3039 Td
(ously)Tj
2.313 0 Td
(that)Tj
1.7802 0 Td
(a)Tj
0.6519 0 Td
(multiple-dose)Tj
5.7373 0 Td
(series)Tj
2.4264 0 Td
(of)Tj
1.0148 0 Td
(SRL172,)Tj
3.5093 0 Td
(an)Tj
1.2019 0 Td
(inactivated,)Tj
4.8245 0 Td
(whole-cell)Tj
4.2973 0 Td
(vaccine)Tj
3.1918 0 Td
(prepared)Tj
3.8098 0 Td
(from)Tj
2.2053 0 Td
(a)Tj
-36.9635 -1.2983 Td
(non-tuberculous)Tj
6.8938 0 Td
(mycobacterium)Tj
6.4969 0 Td
(was)Tj
1.7008 0 Td
(safe,)Tj
1.9502 0 Td
(well-tolerated)Tj
5.7033 0 Td
(and)Tj
1.7291 0 Td
(immunogenic)Tj
5.8337 0 Td
(in)Tj
1.0375 0 Td
(humans)Tj
3.4412 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
-34.7865 -1.2982 Td
(10)Tj
0 g
(].)Tj
1.7347 0 Td
(A)Tj
0.9071 0 Td
(randomized)Tj
5.057 0 Td
(controlled)Tj
4.32 0 Td
(Phase)Tj
2.5228 0 Td
(III)Tj
1.2416 0 Td
(trial)Tj
1.8368 0 Td
(in)Tj
1.0375 0 Td
(Tanzania)Tj
3.9118 0 Td
(demonstrated)Tj
5.7599 0 Td
(that)Tj
1.7745 0 Td
(boosting)Tj
3.685 0 Td
(with)Tj
-33.7887 -1.3039 Td
(SRL172)Tj
3.2824 0 Td
(protected)Tj
4.0082 0 Td
(against)Tj
3.0274 0 Td
(culture-confirmed)Tj
7.5685 0 Td
(tuberculosis)Tj
5.0399 0 Td
(in)Tj
1.0375 0 Td
(HIV-infected)Tj
5.5729 0 Td
(adults)Tj
2.6135 0 Td
(who)Tj
1.9389 0 Td
(had)Tj
-34.0892 -1.2983 Td
(received)Tj
3.5319 0 Td
(BCG)Tj
2.1827 0 Td
(at)Tj
0.9524 0 Td
(birth)Tj
2.1883 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(].)Tj
-7.6591 -1.2983 Td
(DAR-901,)Tj
4.2689 0 Td
(a)Tj
0.652 0 Td
(vaccine)Tj
3.1974 0 Td
(produced)Tj
4.0422 0 Td
(from)Tj
2.2054 0 Td
(the)Tj
1.474 0 Td
(same)Tj
2.2563 0 Td
(seed)Tj
1.9559 0 Td
(strain)Tj
2.5002 0 Td
(using)Tj
2.3867 0 Td
(a)Tj
0.6577 0 Td
(new,)Tj
2.0976 0 Td
(scalable)Tj
3.2995 0 Td
(manufactur-)Tj
-32.19 -1.3039 Td
(ing)Tj
1.5023 0 Td
(method,)Tj
3.549 0 Td
(has)Tj
1.542 0 Td
(entered)Tj
3.2371 0 Td
(clinical)Tj
3.0728 0 Td
(development.)Tj
5.6352 0 Td
(In)Tj
1.1112 0 Td
(this)Tj
1.6724 0 Td
(report,)Tj
2.9367 0 Td
(we)Tj
1.3266 0 Td
(present)Tj
3.1634 0 Td
(the)Tj
1.4684 0 Td
(results)Tj
2.8119 0 Td
(of)Tj
1.0148 0 Td
(preclini-)Tj
-34.0438 -1.2982 Td
(cal)Tj
1.3209 0 Td
(studies)Tj
2.9877 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(immunogenicity)Tj
6.8598 0 Td
(and)Tj
1.7291 0 Td
(protective)Tj
4.2066 0 Td
(efficacy)Tj
3.2202 0 Td
(of)Tj
1.0148 0 Td
(DAR-901)Tj
4.0421 0 Td
(in)Tj
1.0318 0 Td
(mice.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 366.633 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Methods)Tj
ET
Q
q
0.83 0.64 0.02 0 k
1 j
1 J
0 w
10 0 0 10 200.0125 349.6251 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Fig)Tj
1.4796 0 Td
(1)Tj
0 g
0.6973 0 Td
(depicts)Tj
3.0331 0 Td
(a)Tj
0.6576 0 Td
(schedule)Tj
3.6794 0 Td
(of)Tj
1.0148 0 Td
(study)Tj
2.3924 0 Td
(visits)Tj
2.228 0 Td
(and)Tj
1.7291 0 Td
(assessments.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 320.9952 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Mice)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 211.9748 303.9874 cm
BT
/F14 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Immunogenicity)Tj
7.1829 0 Td
(Experiments.)Tj
/F8 1 Tf
6.3326 0 Td
(We)Tj
1.61 0 Td
(obtained)Tj
3.7304 0 Td
(female)Tj
2.8573 0 Td
(810)Tj
2.16 0 Td
(week)Tj
2.2507 0 Td
(old)Tj
1.4967 0 Td
(C57BL/6)Tj
3.7587 0 Td
(and)Tj
1.7348 0 Td
(BALB/c)Tj
-34.3103 -1.2982 Td
(mice)Tj
2.1543 0 Td
(from)Tj
2.2053 0 Td
(Jackson)Tj
3.3165 0 Td
(Laboratory)Tj
4.6431 0 Td
(\(Bar)Tj
1.9446 0 Td
(Harbor,)Tj
3.4072 0 Td
(Maine\))Tj
3.1238 0 Td
(and)Tj
1.7291 0 Td
(maintained)Tj
4.7905 0 Td
(them)Tj
2.2904 0 Td
(in)Tj
1.0318 0 Td
(pathogen-free)Tj
-30.6366 -1.2983 Td
(conditions.)Tj
4.6997 0 Td
(Animal)Tj
3.2202 0 Td
(experiments)Tj
5.1363 0 Td
(were)Tj
2.126 0 Td
(reviewed)Tj
3.7927 0 Td
(and)Tj
1.7292 0 Td
(approved)Tj
3.9741 0 Td
(by)Tj
1.1849 0 Td
(the)Tj
1.4683 0 Td
(Noble)Tj
2.6419 0 Td
(Life)Tj
1.7348 0 Td
(Sciences)Tj
3.5659 0 Td
(Insti-)Tj
-35.274 -1.3039 Td
(tutional)Tj
3.3448 0 Td
(Animal)Tj
3.2201 0 Td
(Care)Tj
2.1147 0 Td
(and)Tj
1.7291 0 Td
(Use)Tj
1.7405 0 Td
(Committee)Tj
4.7394 0 Td
(\(IACUC\).)Tj
4.2123 0 Td
(We)Tj
1.6101 0 Td
(conducted)Tj
4.4277 0 Td
(experiments)Tj
5.1363 0 Td
(according)Tj
4.1896 0 Td
(to)Tj
-36.4646 -1.2983 Td
(guidelines)Tj
4.2746 0 Td
(set)Tj
1.3039 0 Td
(out)Tj
1.5534 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.474 0 Td
(Association)Tj
4.8755 0 Td
(for)Tj
1.389 0 Td
(Assessment)Tj
4.8586 0 Td
(and)Tj
1.7291 0 Td
(Accreditation)Tj
5.6976 0 Td
(of)Tj
1.0148 0 Td
(Laboratory)Tj
4.6431 0 Td
(Animal)Tj
-33.9928 -1.2982 Td
(Care)Tj
2.1089 0 Td
(International)Tj
5.4878 0 Td
(\(AAALAC\).)Tj
5.0627 0 Td
(Prior)Tj
2.296 0 Td
(to)Tj
1.0262 0 Td
(vaccine)Tj
3.1918 0 Td
(administration)Tj
6.1738 0 Td
(at)Tj
0.9524 0 Td
(weeks)Tj
2.6079 0 Td
(0,)Tj
0.9184 0 Td
(2)Tj
0.6973 0 Td
(and)Tj
1.7291 0 Td
(4,)Tj
0.9241 0 Td
(mice)Tj
2.1487 0 Td
(were)Tj
-35.3251 -1.3039 Td
(anesthetized)Tj
5.1646 0 Td
(using)Tj
2.3925 0 Td
(tribromoethanol)Tj
6.8541 0 Td
(250mg/kg)Tj
4.2179 0 Td
(intraperitoneally.)Tj
7.1036 0 Td
(Immunogenicity)Tj
6.9335 0 Td
(assessments)Tj
-32.6662 -1.2983 Td
(were)Tj
2.1146 0 Td
(performed)Tj
4.4673 0 Td
(in)Tj
1.0262 0 Td
(mice)Tj
2.1486 0 Td
(sacrificed)Tj
4.0025 0 Td
(by)Tj
1.1792 0 Td
(carbon)Tj
3.0047 0 Td
(dioxide)Tj
3.1975 0 Td
(asphyxiation)Tj
5.2951 0 Td
(at)Tj
0.9467 0 Td
(weeks)Tj
2.6079 0 Td
(2,)Tj
0.9127 0 Td
(4)Tj
0.6917 0 Td
(and)Tj
1.7235 0 Td
(6.)Tj
0.9184 0 Td
(Animals)Tj
-34.2366 -1.2983 Td
(were)Tj
2.1202 0 Td
(monitored)Tj
4.4901 0 Td
(continuously)Tj
5.4368 0 Td
(throughout)Tj
4.7792 0 Td
(experimental)Tj
5.4595 0 Td
(procedures,)Tj
4.8982 0 Td
(routinely)Tj
3.8665 0 Td
(following)Tj
3.9798 0 Td
(any)Tj
-35.0303 -1.3039 Td
(procedures)Tj
4.6714 0 Td
(\(e.g.,)Tj
2.126 0 Td
(to)Tj
1.0261 0 Td
(ensure)Tj
2.8743 0 Td
(full)Tj
1.5307 0 Td
(recovery)Tj
3.6454 0 Td
(from)Tj
2.2053 0 Td
(anesthesia\),)Tj
4.8642 0 Td
(and)Tj
1.7348 0 Td
(otherwise)Tj
4.0819 0 Td
(on)Tj
1.2756 0 Td
(a)Tj
0.6519 0 Td
(daily)Tj
2.1487 0 Td
(basis.)Tj
2.3754 0 Td
(No)Tj
-35.2117 -1.2983 Td
(procedures)Tj
4.6714 0 Td
(involved)Tj
3.651 0 Td
(in)Tj
1.0375 0 Td
(this)Tj
1.6724 0 Td
(study)Tj
2.3868 0 Td
(caused)Tj
2.9196 0 Td
(more)Tj
2.3414 0 Td
(than)Tj
2.0296 0 Td
(momentary)Tj
4.8983 0 Td
(pain/distress)Tj
5.2837 0 Td
(\(e.g.,)Tj
2.126 0 Td
(subcutane-)Tj
-33.0177 -1.2982 Td
(ous)Tj
1.6157 0 Td
(immunizations\).)Tj
6.8654 0 Td
(Our)Tj
1.8652 0 Td
(IACUC)Tj
3.3052 0 Td
(protocol)Tj
3.6 0 Td
(allows)Tj
2.6929 0 Td
(the)Tj
1.474 0 Td
(vivarium)Tj
3.8154 0 Td
(to)Tj
1.0261 0 Td
(euthanize)Tj
4.0819 0 Td
(any)Tj
1.6554 0 Td
(animals)Tj
3.3335 0 Td
(that)Tj
-35.3307 -1.2983 Td
(appear)Tj
2.9139 0 Td
(to)Tj
1.0262 0 Td
(be)Tj
1.1508 0 Td
(in)Tj
1.0375 0 Td
(any)Tj
1.6554 0 Td
(pain)Tj
1.9899 0 Td
(or)Tj
1.0942 0 Td
(distress.)Tj
3.4186 0 Td
(No)Tj
1.4626 0 Td
(animals)Tj
3.3279 0 Td
(died)Tj
1.9672 0 Td
(prior)Tj
2.2564 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(experimental)Tj
5.4594 0 Td
(endpoint;)Tj
4.0819 0 Td
(there)Tj
-35.3364 -1.3039 Td
(were)Tj
2.1202 0 Td
(no)Tj
1.2756 0 Td
(observations)Tj
5.2611 0 Td
(of)Tj
1.0148 0 Td
(significant)Tj
4.388 0 Td
(pain/distress.)Tj
/F14 1 Tf
-12.8635 -1.2983 Td
(Challenge)Tj
4.3766 0 Td
(experiments.)Tj
/F8 1 Tf
6.1852 0 Td
(We)Tj
1.61 0 Td
(obtained)Tj
3.7304 0 Td
(specific)Tj
3.1918 0 Td
(pathogen-free,)Tj
6.0264 0 Td
(female)Tj
2.8517 0 Td
(69)Tj
1.6894 0 Td
(weeks)Tj
2.6079 0 Td
(old)Tj
-33.4656 -1.2982 Td
(C57BL/6)Tj
3.7587 0 Td
(mice)Tj
2.1543 0 Td
(from)Tj
2.2053 0 Td
(Charles)Tj
3.2428 0 Td
(River)Tj
2.3584 0 Td
(\(United)Tj
3.3619 0 Td
(Kingdom\).)Tj
4.5978 0 Td
(All)Tj
1.3946 0 Td
(animal)Tj
2.9707 0 Td
(procedures)Tj
4.6715 0 Td
(were)Tj
2.1259 0 Td
(approved)Tj
-32.8419 -1.3039 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4683 0 Td
(National)Tj
3.6963 0 Td
(Institute)Tj
3.583 0 Td
(for)Tj
1.3833 0 Td
(Biological)Tj
4.1612 0 Td
(Standards)Tj
4.201 0 Td
(and)Tj
1.7291 0 Td
(Control)Tj
3.3618 0 Td
(ethics)Tj
2.5229 0 Td
(committee)Tj
4.5014 0 Td
(and)Tj
1.7291 0 Td
(were)Tj
2.1203 0 Td
(in)Tj
-35.6369 -1.2983 Td
(accordance)Tj
4.7338 0 Td
(with)Tj
2.0012 0 Td
(UK)Tj
1.6271 0 Td
(Home)Tj
2.7382 0 Td
(Office)Tj
2.6589 0 Td
(\(Scientific)Tj
4.2406 0 Td
(Procedures\))Tj
5.057 0 Td
(Act)Tj
1.6214 0 Td
(1986.)Tj
2.3527 0 Td
(Mice)Tj
2.2224 0 Td
(were)Tj
2.126 0 Td
(primed)Tj
3.1464 0 Td
(with)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 442.4881 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Protective)Tj
4.5921 0 Td
(TB)Tj
1.4882 0 Td
(Vaccine)Tj
3.7134 0 Td
(Immunogeni)Tj
5.4142 0 Td
(city)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.4748 0 Td
(DOI:10.137)Tj
5.0387 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.0168)Tj
3.5434 0 Td
(521)Tj
2.6362 0 Td
(December)Tj
4.7622 0 Td
(20,)Tj
1.5874 0 Td
(2016)Tj
36.7515 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
28 0 obj
<>stream
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
endstream
endobj
33 0 obj
<>stream
endstream
endobj
34 0 obj
<>stream
endstream
endobj
35 0 obj
<>stream
endstream
endobj
36 0 obj
<>stream
endstream
endobj
37 0 obj
<>stream
endstream
endobj
38 0 obj
<>stream
endstream
endobj
39 0 obj
<>stream
endstream
endobj
40 0 obj
<>stream
endstream
endobj
41 0 obj
<>stream
BT
66.402 0 Td
(12)Tj
ET
Q
endstream
endobj
42 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 13 0 R/Annots 46 0 R/Contents 47 0 R/TrimBox[0 0 612 792]>>
endobj
45 0 obj
<>stream
JFIF C
$, !$4.763.22:ASF:=N>22HbINVX]^]8EfmeZlS[]Y C**Y;2;YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY
9"
} !1AQa"q2#BR$3br
%&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz
w !1AQaq"2B #3Rbr
$4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ? wsgZn@-$mn8?zsbey5_@?OW_PS2Z\KnTNTȯ. +} 5_[ i
9 I_E {/'/k,4Gf9$Ok7LұY"A3|fτ:uZZҬ