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David J. Gasper, Brandon Neldner, Erin H. Plisch, Hani Rustom, Emily Carrow, Hirotaka Imai, Yoshihiro Kawaoka, M. Suresh
Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines
www.plospathogens.org
www.plospathogens.org
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(27)Tj
0 g
(])Tj
1.5137 0 Td
(By)Tj
1.2529 0 Td
(contrast,)Tj
3.6907 0 Td
(inactivated)Tj
4.5921 0 Td
(viruses)Tj
2.9876 0 Td
(and)Tj
1.7291 0 Td
(their)Tj
2.109 0 Td
(subunits)Tj
3.617 0 Td
(are)Tj
1.4513 0 Td
(comparatively)Tj
5.8733 0 Td
(safe,)Tj
-35.7615 -1.2982 Td
(and)Tj
1.7291 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1508 0 Td
(used)Tj
2.058 0 Td
(in)Tj
1.0375 0 Td
(at-risk)Tj
2.7949 0 Td
(populations.)Tj
5.1817 0 Td
(However,)Tj
4.0761 0 Td
(non-replicating)Tj
6.4346 0 Td
(antigens)Tj
3.566 0 Td
(are)Tj
1.4513 0 Td
(intrinsically)Tj
-31.1071 -1.3039 Td
(poor)Tj
2.1203 0 Td
(immunogens)Tj
5.5105 0 Td
(that)Tj
1.7745 0 Td
(primarily)Tj
3.9685 0 Td
(generate)Tj
3.6113 0 Td
(humoral)Tj
3.6509 0 Td
(responses,)Tj
4.3199 0 Td
(even)Tj
2.0693 0 Td
(when)Tj
2.4038 0 Td
(adjuvants)Tj
4.0648 0 Td
(are)Tj
1.4514 0 Td
(added)Tj
-34.9452 -1.2983 Td
(to)Tj
1.0261 0 Td
(enhance)Tj
3.549 0 Td
(immunogenicity.[)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
8.6002 0 Td
(28)Tj
0 g
(])Tj
1.5081 0 Td
(Few)Tj
1.8538 0 Td
(modern)Tj
3.4185 0 Td
(adjuvants)Tj
4.0648 0 Td
(have)Tj
2.058 0 Td
(been)Tj
2.1259 0 Td
(reported)Tj
3.6567 0 Td
(to)Tj
1.0261 0 Td
(safely)Tj
2.4265 0 Td
(elicit)Tj
-35.3137 -1.2983 Td
(cell-mediated)Tj
5.6296 0 Td
(immunity,)Tj
4.4503 0 Td
(and)Tj
1.7291 0 Td
(none)Tj
2.2451 0 Td
(of)Tj
1.0148 0 Td
(those)Tj
2.3414 0 Td
(are)Tj
1.4456 0 Td
(currently)Tj
3.889 0 Td
(licensed)Tj
3.4413 0 Td
(for)Tj
1.3833 0 Td
(routine)Tj
3.1634 0 Td
(use)Tj
1.5307 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(U.S.)Tj
-34.7694 -1.2982 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2586 0 Td
(15)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.4003 0 Td
(26)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.3946 0 Td
(28)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(38)Tj
0 g
(])Tj
2.982 0 Td
(Most)Tj
2.2791 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2507 0 Td
(adjuvants)Tj
4.0648 0 Td
(function)Tj
3.6282 0 Td
(as)Tj
1.0148 0 Td
(simple)Tj
2.8517 0 Td
(ligands)Tj
3.0727 0 Td
(for)Tj
1.3833 0 Td
(pattern)Tj
3.1124 0 Td
(recognition)Tj
-31.708 -1.3039 Td
(receptors,)Tj
4.1385 0 Td
(or)Tj
1.0999 0 Td
(are)Tj
1.4513 0 Td
(immune)Tj
3.6227 0 Td
(stimulating)Tj
4.7565 0 Td
(complexes)Tj
4.4049 0 Td
(that)Tj
1.7801 0 Td
(act)Tj
1.372 0 Td
(on)Tj
1.2756 0 Td
(a)Tj
0.6576 0 Td
(variety)Tj
2.9197 0 Td
(of)Tj
1.0148 0 Td
(receptors)Tj
3.9174 0 Td
(on)Tj
1.2756 0 Td
(many)Tj
2.4775 0 Td
(cell)Tj
-36.1641 -1.2983 Td
(types.)Tj
1.1962 -1.2983 Td
(Adjuplex)Tj
3.8721 0 Td
(\(ADJ\))Tj
2.6475 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(carbomer-lecithin-based)Tj
10.0345 0 Td
(adjuvant)Tj
3.702 0 Td
(demonstrated)Tj
5.76 0 Td
(to)Tj
1.0261 0 Td
(elicit)Tj
2.143 0 Td
(robust)Tj
-31.8838 -1.3039 Td
(humoral)Tj
3.651 0 Td
(immunity)Tj
4.2236 0 Td
(and)Tj
1.7291 0 Td
(T-cell)Tj
2.5228 0 Td
(responses)Tj
4.0932 0 Td
(to)Tj
1.0262 0 Td
(subcutaneous)Tj
5.6691 0 Td
(IAV)Tj
1.9389 0 Td
(subunit)Tj
3.2542 0 Td
(vaccines)Tj
3.5546 0 Td
(in)Tj
1.0374 0 Td
(mice.[)Tj
0.83 0.64 0.02 0 k
(39)Tj
0 g
(])Tj
-32.7001 -1.2983 Td
(Here)Tj
2.2053 0 Td
(we)Tj
1.3266 0 Td
(report)Tj
2.7099 0 Td
(that)Tj
1.7802 0 Td
(intramuscular,)Tj
6.0718 0 Td
(subcutaneous,)Tj
5.8959 0 Td
(and)Tj
1.7291 0 Td
(intranasal)Tj
4.1612 0 Td
(administration)Tj
6.1682 0 Td
(of)Tj
1.0148 0 Td
(ADJ-adju-)Tj
-33.063 -1.2982 Td
(vanted)Tj
2.9083 0 Td
(non-replicating)Tj
6.4346 0 Td
(antigens)Tj
3.566 0 Td
(generated)Tj
4.1329 0 Td
(robust)Tj
2.7948 0 Td
(antigen-specific)Tj
6.5253 0 Td
(CTL)Tj
2.0353 0 Td
(responses)Tj
4.0932 0 Td
(in)Tj
1.0375 0 Td
(mice.)Tj
-33.5279 -1.3039 Td
(Systemic)Tj
3.7417 0 Td
(CTL)Tj
2.0353 0 Td
(memory)Tj
3.6113 0 Td
(was)Tj
1.7007 0 Td
(induced)Tj
3.464 0 Td
(regardless)Tj
4.2065 0 Td
(of)Tj
1.0147 0 Td
(whether)Tj
3.4753 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.126 0 Td
(vaccinated)Tj
4.4504 0 Td
(via)Tj
1.3776 0 Td
(subcuta-)Tj
-33.3578 -1.2983 Td
(neous,)Tj
2.8119 0 Td
(intramuscular)Tj
5.8507 0 Td
(or)Tj
1.0998 0 Td
(intranasal)Tj
4.1613 0 Td
(routes,)Tj
2.9366 0 Td
(however,)Tj
3.8324 0 Td
(only)Tj
1.9785 0 Td
(intranasal)Tj
4.1613 0 Td
(vaccination)Tj
4.8302 0 Td
(provided)Tj
3.8154 0 Td
(pro-)Tj
-35.4781 -1.2983 Td
(tection)Tj
2.9877 0 Td
(against)Tj
3.0274 0 Td
(influenza)Tj
3.9174 0 Td
(viral)Tj
1.9899 0 Td
(challenge,)Tj
4.1839 0 Td
(and)Tj
1.7292 0 Td
(correlated)Tj
4.2461 0 Td
(with)Tj
2.0013 0 Td
(an)Tj
1.2019 0 Td
(enhancement)Tj
5.6409 0 Td
(of)Tj
1.0148 0 Td
(CD103)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 547.6535 373.833 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(+)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 356.4283 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(CD69)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 223.4834 360.8503 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(+)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 230.0598 356.4283 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(CXCR3)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 260.7874 360.8503 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(+)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 267.3637 356.4283 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(T)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 273.4866 354.7275 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(RM)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 286.9795 356.4283 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(and)Tj
1.7347 0 Td
(airway)Tj
2.863 0 Td
(memory)Tj
3.617 0 Td
(T)Tj
0.8277 0 Td
(cells)Tj
1.9219 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(lung.)Tj
2.2337 0 Td
(Thus,)Tj
2.4718 0 Td
(ADJ)Tj
1.9729 0 Td
(can)Tj
1.6214 0 Td
(be)Tj
1.1509 0 Td
(used)Tj
2.0636 0 Td
(to)Tj
1.0261 0 Td
(induce)Tj
-34.7071 -1.3039 Td
(systemic)Tj
3.6283 0 Td
(and/or)Tj
2.9367 0 Td
(mucosal)Tj
3.5375 0 Td
(CTL)Tj
2.0353 0 Td
(memory)Tj
3.617 0 Td
(to)Tj
1.0261 0 Td
(non-replicating)Tj
6.4346 0 Td
(antigens,)Tj
3.7927 0 Td
(and)Tj
1.7292 0 Td
(by)Tj
1.1792 0 Td
(tailoring)Tj
3.6283 0 Td
(the)Tj
1.4683 0 Td
(route)Tj
-35.0132 -1.2982 Td
(of)Tj
1.0148 0 Td
(vaccine)Tj
3.1918 0 Td
(delivery)Tj
3.3902 0 Td
(we)Tj
1.3265 0 Td
(can)Tj
1.6271 0 Td
(engender)Tj
3.9515 0 Td
(CTL-based)Tj
4.6374 0 Td
(protective)Tj
4.2066 0 Td
(immunity)Tj
4.2236 0 Td
(against)Tj
3.0274 0 Td
(systemic)Tj
3.6283 0 Td
(and)Tj
-34.2252 -1.2983 Td
(mucosal)Tj
3.5376 0 Td
(pathogens.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 288 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F0 1 Tf
0 -1.5023 Td
(Adjuplex)Tj
4.0016 0 Td
(induces)Tj
3.6189 0 Td
(robust)Tj
2.9717 0 Td
(expansion)Tj
4.715 0 Td
(of)Tj
1.0488 0 Td
(antigen-specif)Tj
6.1418 0 Td
(ic)Tj
0.9354 0 Td
(CD8)Tj
2.1969 0 Td
(and)Tj
1.8614 0 Td
(CD4)Tj
2.2016 0 Td
(T)Tj
-29.6931 -1.1622 Td
(cells)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 239.0173 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(The)Tj
1.7801 0 Td
(carbomer-lecithin)Tj
7.4324 0 Td
(based)Tj
2.4718 0 Td
(adjuvant)Tj
3.702 0 Td
(ADJ)Tj
1.9672 0 Td
(was)Tj
1.7008 0 Td
(previously)Tj
4.3483 0 Td
(demonstrated)Tj
5.7657 0 Td
(to)Tj
1.0204 0 Td
(induce)Tj
2.9424 0 Td
(humoral)Tj
-33.1311 -1.3039 Td
(responses)Tj
4.0932 0 Td
(in)Tj
1.0374 0 Td
(a)Tj
0.652 0 Td
(wide)Tj
2.1203 0 Td
(range)Tj
2.4661 0 Td
(of)Tj
1.0148 0 Td
(species.[)Tj
0.83 0.64 0.02 0 k
(39)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(44)Tj
0 g
(].)Tj
6.548 0 Td
(Here,)Tj
2.4264 0 Td
(using)Tj
2.3925 0 Td
(the)Tj
1.4683 0 Td
(tractable)Tj
3.6567 0 Td
(chicken)Tj
3.3335 0 Td
(ovalbumin)Tj
-31.2092 -1.2982 Td
(\(OVA\))Tj
3.0217 0 Td
(antigen)Tj
3.2088 0 Td
(model,)Tj
2.9707 0 Td
(we)Tj
1.3266 0 Td
(investigated)Tj
4.9889 0 Td
(whether)Tj
3.4753 0 Td
(ADJ)Tj
1.9729 0 Td
(\(confirmed)Tj
4.7338 0 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1509 0 Td
(endotoxin-free\))Tj
6.5083 0 Td
(can)Tj
-34.384 -1.2983 Td
(elicit)Tj
2.1429 0 Td
(antigen-specific)Tj
6.5253 0 Td
(CD4)Tj
2.0977 0 Td
(and)Tj
1.7291 0 Td
(CD8)Tj
2.0976 0 Td
(T)Tj
0.8277 0 Td
(cell)Tj
1.5647 0 Td
(responses.)Tj
4.3143 0 Td
(OVA-specific)Tj
5.6693 0 Td
(na)Tj
/F11 1 Tf
[()]TJ
/F7 1 Tf
(ve)Tj
2.3357 0 Td
(CTLs)Tj
2.3925 0 Td
(and)Tj
1.7348 0 Td
(helper)Tj
2.7269 0 Td
(T)Tj
-36.1585 -1.3039 Td
(\(T)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 209.537 185.3291 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(H)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 215.2629 186.9732 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(\))Tj
0.5612 0 Td
(cells)Tj
1.9162 0 Td
(are)Tj
1.4513 0 Td
(infrequent)Tj
4.4221 0 Td
(in)Tj
1.0374 0 Td
(na)Tj
/F11 1 Tf
[()]TJ
/F7 1 Tf
(ve)Tj
2.3358 0 Td
(mice,)Tj
2.3811 0 Td
(and)Tj
1.7291 0 Td
(to)Tj
1.0261 0 Td
(enhance)Tj
3.549 0 Td
(assay)Tj
2.262 0 Td
(sensitivity)Tj
4.2236 0 Td
(we)Tj
1.3266 0 Td
(initially)Tj
3.2485 0 Td
(employed)Tj
-32.995 -1.2982 Td
(adoptive)Tj
3.6509 0 Td
(transfer)Tj
3.3109 0 Td
(techniques.)Tj
4.7565 0 Td
(To)Tj
1.3379 0 Td
(assess)Tj
2.5228 0 Td
(the)Tj
1.4684 0 Td
(activation)Tj
4.1499 0 Td
(and)Tj
1.7291 0 Td
(expansion)Tj
4.2973 0 Td
(of)Tj
1.0148 0 Td
(antigen-specific)Tj
6.5253 0 Td
(CD8)Tj
2.092 0 Td
(T)Tj
-36.8558 -1.2983 Td
(cells,)Tj
2.1429 0 Td
(we)Tj
1.3266 0 Td
(adoptively)Tj
4.354 0 Td
(transferred)Tj
4.6374 0 Td
(OVA)Tj
2.3471 0 Td
(SIINFEKL-specific)Tj
7.7385 0 Td
(na)Tj
/F11 1 Tf
[()]TJ
/F7 1 Tf
(ve)Tj
2.3415 0 Td
(TCR)Tj
2.1146 0 Td
(transgenic)Tj
4.3596 0 Td
(OT-1)Tj
2.4038 0 Td
(CD8)Tj
2.0976 0 Td
(T)Tj
-35.8636 -1.2982 Td
(cells)Tj
1.9218 0 Td
(\(Thy1.1\))Tj
3.668 0 Td
(into)Tj
1.8425 0 Td
(congenic)Tj
3.8268 0 Td
(Thy1.2)Tj
2.9877 0 Td
(B6)Tj
1.2755 0 Td
(mice.)Tj
2.3811 0 Td
(One)Tj
1.9389 0 Td
(day)Tj
1.6328 0 Td
(after)Tj
2.0352 0 Td
(cell)Tj
1.5591 0 Td
(transfer,)Tj
3.5433 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(immunized)Tj
-32.8873 -1.304 Td
(by)Tj
1.1792 0 Td
(intramuscular)Tj
5.8506 0 Td
(\(I/M\))Tj
2.4661 0 Td
(injections)Tj
4.1159 0 Td
(with)Tj
2.0013 0 Td
(100)Tj
/F11 1 Tf
1.644 0 Td
[()]TJ
/F7 1 Tf
(g)Tj
1.1962 0 Td
(OVA)Tj
2.3414 0 Td
(in)Tj
1.0375 0 Td
(PBS)Tj
1.8369 0 Td
(with)Tj
1.9955 0 Td
(and)Tj
1.7292 0 Td
(without)Tj
3.3278 0 Td
(ADJ)Tj
1.9729 0 Td
(20%)Tj
1.9276 0 Td
(v/v)Tj
1.4626 0 Td
(or)Tj
-36.0847 -1.2982 Td
(Alum)Tj
2.4944 0 Td
(50%)Tj
1.9332 0 Td
(v/v.)Tj
1.6838 0 Td
(On)Tj
1.5137 0 Td
(day)Tj
1.6384 0 Td
(7)Tj
0.6916 0 Td
(after)Tj
2.0353 0 Td
(immunization,)Tj
6.1625 0 Td
(activated)Tj
3.7814 0 Td
(OT-I)Tj
2.2677 0 Td
(cells)Tj
1.9219 0 Td
(in)Tj
1.0374 0 Td
(spleen)Tj
2.7383 0 Td
(were)Tj
2.1259 0 Td
(enumerated)Tj
-32.0255 -1.2983 Td
(by)Tj
1.1792 0 Td
(flow)Tj
1.9445 0 Td
(cytometry.)Tj
4.4957 0 Td
(Data)Tj
2.126 0 Td
(in)Tj
0.83 0.64 0.02 0 k
1.0374 0 Td
(Fig)Tj
1.4797 0 Td
(1A)Tj
1.3776 0 Td
(and)Tj
1.7292 0 Td
(1B)Tj
0 g
1.2756 0 Td
(illustrate)Tj
3.6963 0 Td
(the)Tj
1.4683 0 Td
(potent)Tj
2.812 0 Td
(activation)Tj
4.1556 0 Td
(and)Tj
1.7291 0 Td
(clonal)Tj
2.6249 0 Td
(expansion)Tj
-33.1311 -1.3039 Td
(of)Tj
1.0148 0 Td
(donor)Tj
2.6815 0 Td
(OT-1)Tj
2.4037 0 Td
(CD8)Tj
2.092 0 Td
(T)Tj
0.8334 0 Td
(cells)Tj
1.9219 0 Td
(in)Tj
1.0318 0 Td
(spleen)Tj
2.7439 0 Td
(of)Tj
1.0148 0 Td
(ADJ)Tj
1.9672 0 Td
(mice)Tj
2.1543 0 Td
(\(35100)Tj
3.4583 0 Td
(fold)Tj
1.7858 0 Td
(higher\),)Tj
3.3675 0 Td
(as)Tj
1.0148 0 Td
(compared)Tj
4.2463 0 Td
(to)Tj
1.0261 0 Td
(OT-I)Tj
-34.7581 -1.2983 Td
(CD8)Tj
2.0919 0 Td
(T)Tj
0.8334 0 Td
(cells)Tj
1.9218 0 Td
(in)Tj
1.0318 0 Td
(mice)Tj
2.1544 0 Td
(vaccinated)Tj
4.456 0 Td
(with)Tj
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