Development of newborn and infant vaccines

Science Translational Medicine

Volumn 3, Issue 90, 2011, Pages

  Sanchez Schmitz, Guzman ^a,b   Levy, Ofer ^a,b  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BCG VACCINE; DIPHTHERIA PERTUSSIS TETANUS HAEMOPHILUS INFLUENZAE TYPE B VACCINE; DIPHTHERIA PERTUSSIS TETANUS HEPATITIS B VACCINE; HEPATITIS B VACCINE; HUMAN IMMUNODEFICIENCY VIRUS VACCINE; IMMUNOLOGICAL ADJUVANT; MEASLES VACCINE; ORAL POLIOMYELITIS VACCINE; PERTUSSIS VACCINE; PNEUMOCOCCUS VACCINE; ROTAVIRUS VACCINE; VACCINE;

ADAPTIVE IMMUNITY; AGE DISTRIBUTION; AGE SPECIFIC CARE; ANTIGEN PRESENTING CELL; B LYMPHOCYTE; CHILD HEALTH CARE; CYTOKINE RESPONSE; DRUG ADMINISTRATION ROUTE; DRUG APPROVAL; DRUG EFFICACY; DRUG INDICATION; DRUG SAFETY; HUMAN; HUMORAL IMMUNITY; IMMUNIZATION; INFANT; INFECTION PREVENTION; INNATE IMMUNITY; MILIARY TUBERCULOSIS; NONHUMAN; PRIORITY JOURNAL; REVIEW; SINGLE DRUG DOSE; T LYMPHOCYTE; TUBERCULOUS MENINGITIS; ADULT; ANIMAL; ARTICLE; IMMUNE SYSTEM; IMMUNOLOGY; INFECTION CONTROL; NEWBORN; PRESCHOOL CHILD; VACCINATION;

ADULT; ANIMALS; CHILD, PRESCHOOL; COMMUNICABLE DISEASE CONTROL; HUMANS; IMMUNE SYSTEM; INFANT, NEWBORN; VACCINATION; VACCINES;

EID: 79960082884     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3001880     Document Type: Review

References (83)

1. J. E. Lawn, S. Cousens, J. Zupan; Lancet Neonatal Survival Steering Team, 4 million neonatal deaths: When? Where? Why? Lancet 365, 891-900 (2005).
2. J. Bryce, B. Daelmans, A. Dwivedi, V. Fauveau, J. E. Lawn, E. Mason, H. Newby, A. Shankar, A. Starrs, T. Wardlaw; Countdown Coverage Writing Group; Countdown to 2015 Core Group, Countdown to 2015 for maternal, newborn, and child survival: The 2008 report on tracking coverage of interventions. Lancet 371, 1247-1258 (2008).
3. WHO, Neonatal and perinatal mortality: Country, regional and global estimates. 2006: Geneva.
4. A. Burton, R. Monasch, B. Lautenbach, M. Gacic-Dobo, M. Neill, R. Karimov, L. Wolfson, G. Jones, M. Birmingham, WHO and UNICEF estimates of national infant immunization coverage: Methods and processes. Bull. World Health Organ. 87, 535-541 (2009).
5. D. Thaver, A. K. Zaidi, Burden of neonatal infections in developing countries: A review of evidence from community-based studies. Pediatr. Infect. Dis. J. 28 (suppl.), S3-S9 (2009).
6. S. A. Gall, Maternal immunization to protect the mother and neonate. Expert Rev. Vaccines 4, 813-818 (2005).
7. C. A. Siegrist, in The Vaccine Book, B. Bloom, P. H. Lambert, Eds. (Academic Press, Boston, 2003), pp. 73-83.
8. CDC, Recommended Immunization Schedule for Persons Aged 0 Through 6 Years - United States 2010, Department of Health and Human Services, Centers for Disease Control and Prevention http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5851a6.htm.
9. P. Marrack, A. S. McKee, M. W. Munks, Towards an understanding of the adjuvant action of aluminium. Nat. Rev. Immunol. 9, 287-293 (2009).
10. E. E. Mast, H. S. Margolis, A. E. Fiore, E. W. Brink, S. T. Goldstein, S. A. Wang, L. A. Moyer, B. P. Bell, M. J. AlterAdvisory Committee on Immunization Practices (ACIP), A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP), part 1: immunization of infants, children, and adolescents. MMWR Recomm. Rep. 54, (RR-16), 1-31 (2005).
11. P. Andersen, T. M. Doherty, The success and failure of BCG -Implications for a novel tuberculosis vaccine. Nat. Rev. Microbiol. 3, 656-662 (2005).
12. K. A. Heldwein, M. D. Liang, T. K. Andresen, K. E. Thomas, A. M. Marty, N. Cuesta, S. N. Vogel, M. J. Fenton, TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG. J. Leukoc. Biol. 74, 277-286 (2003).
13. J. Vekemans, A. Amedei, M. O. Ota, M. M. D'Elios, T. Goetghebuer, J. Ismaili, M. J. Newport, G. Del Prete, M. Goldman, K. P. W. J. McAdam, A. Mayant, Neonatal bacillus Calmette-Guérin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes. Eur. J. Immunol. 31, 1531-1535 (2001).
14. B. B. Trunz, P. Fine, C. Dye, Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: A meta-analysis and assessment of cost-effectiveness. Lancet 367, 1173-1180 (2006).
15. A. Roth, H. Jensen, M. L. Garly, Q. Djana, C. L. Martins, M. Sodemann, A. Rodrigues, P. Aaby, Low birth weight infants and Calmette-Guérin bacillus vaccination at birth: Community study from Guinea-Bissau. Pediatr. Infect. Dis. J. 23, 544-550 (2004).
16. N. Halsey, A. Galazka, The efficacy of DPT and oral poliomyelitis immunization schedules initiated from birth to 12 weeks of age. Bull. World Health Organ. 63, 1151-1169 (1985).
17. J. Vekemans, M. O. Ota, E. C. Wang, M. Kidd, L. K. Borysiewicz, H. Whittle, K. P. McAdam, G. Morgan, A. Marchant, T cell responses to vaccines in infants: Defective IFN-gamma production after oral polio vaccination. Clin. Exp. Immunol. 127, 495-498 (2002).
18. V. J. Philbin, O. Levy, Immunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes: Basic mechanisms and translational opportunities. Biochem. Soc. Trans. 35, 1485-1491 (2007).
19. A. Demirjian, O. Levy, Safety and efficacy of neonatal vaccination. Eur. J. Immunol. 39, 36-46 (2009).
20. B. Roehr, Whooping cough outbreak hits several US states. BMJ 341, (aug24 2), c4627 (2010).
21. P. A. Di Sant'Agnese, Combined immunization against diphtheria, tetanus and pertussis in newborn infants; production of antibodies in early infancy. Pediatrics 3, 20-33 (1949).
22. R. W. Provenzano, L. H. Wetterlow, C. L. Sullivan, Immunization and antibody response in the newborn infant. I. Pertussis inoculation within twenty-four hours of birth. N. Engl. J. Med. 273, 959-965 (1965).
23. R. W. Provenzano, L. H. Wetterlow, J. Ipsen, Pertussis immunization in pediatric practice and in public health. N. Engl. J. Med. 261, 473-478 (1959).
24. S. David, P. E. Vermeer-de Bondt, N. A. van der Maas, Reactogenicity of infant whole cell pertussis combination vaccine compared with acellular pertussis vaccines with or without simultaneous pneumococcal vaccine in the Netherlands. Vaccine 26, 5883-5887 (2008).
25. N. B. Halasa, A. O'Shea, J. R. Shi, B. J. LaFleur, K. M. Edwards, Poor immune responses to a birth dose of diphtheria, tetanus, and acellular pertussis vaccine. J. Pediatr. 153, 327-332.e1 (2008).
26. M. Knuf, H. J. Schmitt, J. Wolter, L. Schuerman, J. M. Jacquet, D. Kieninger, C. A. Siegrist, F. Zepp, Neonatal vaccination with an acellular pertussis vaccine accelerates the acquisition of pertussis antibodies in infants. J. Pediatr. 152, 655-660, 660.e1 (2008).
27. O. J. White, J. Rowe, P. Richmond, H. Marshall, P. McIntyre, N. Wood, P. G. Holt, Th2-polarisation of cellular immune memory to neonatal pertussis vaccination. Vaccine 28, 2648-2652 (2010).
28. A. H. van den Biggelaar, P. C. Richmond, W. S. Pomat, S. Phuanukoonnon, M. A. Nadal-Sims, C. J. Devitt, P. M. Siba, D. Lehmann, P. G. Holt, Neonatal pneumococcal conjugate vaccine immunization primes T cells for preferential Th2 cytokine expression: A randomized controlled trial in Papua New Guinea. Vaccine 27, 1340-1347 (2009).
29. W. Pomat et al., Alternative pneumococcal vaccination scheduled for high risk populations: Immunogenicity of neoantal pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine in Papua New Guinean children, in Pneumococci and Pneumococcal Diseases Symposium. 2010: Tel Aviv, Israel.
30. T. Vesikari, A. Karvonen, B. D. Forrest, Y. Hoshino, R. M. Chanock, A. Z. Kapikian, Neonatal administration of rhesus rotavirus tetravalent vaccine. Pediatr. Infect. Dis. J. 25, 118-122 (2006).
31. P. H. Dennehy, Rotavirus vaccines: An overview. Clin. Microbiol. Rev. 21, 198-208 (2008).
32. S. Resik, A. Tejeda, P. M. Lago, M. Diaz, A. Carmenates, L. Sarmiento, N. Alemañi, B. Galindo, A. Burton, M. Friede, M. Landaverde, R. W. Sutter, Randomized controlled clinical trial of fractional doses of inactivated poliovirus vaccine administered intradermally by needle-free device in Cuba. J. Infect. Dis. 201, 1344-1352 (2010).
33. P. H. Lambert, P. E. Laurent, Intradermal vaccine delivery: Will new delivery systems transform vaccine administration? Vaccine 26, 3197-3208 (2008).
34. W. Borkowsky, D. Wara, T. Fenton, J. McNamara, M. Kang, L. Mofenson, E. McFarland, C. Cunningham, A. M. Duliege, D. Francis, Y. Bryson, S. Burchett, S. A. Spector, L. M. Frenkel, S. Starr, R. Van Dyke, E. Jimenez, Lymphoproliferative responses to recombinant HIV-1 envelope antigens in neonates and infants receiving gp120 vaccines. AIDS Clinical Trial Group 230 Collaborators. J. Infect. Dis. 181, 890-896 (2000).
35. C. K. Cunningham, D. W. Wara, M. Kang, T. Fenton, E. Hawkins, J. McNamara, L. Mofenson, A. M. Duliege, D. Francis, E. J. McFarland, W. Borkowsky; Pediatric AIDS Clinical Trials Group 230 Collaborators, Safety of 2 recombinant human immunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infected women. Clin. Infect. Dis. 32, 801-807 (2001).
36. R. L. Coffman, A. Sher, R. A. Seder, Vaccine adjuvants: Putting innate immunity to work. Immunity 33, 492-503 (2010).
37. B. N. Lambrecht, M. Kool, M. A. Willart, H. Hammad, Mechanism of action of clinically approved adjuvants. Curr. Opin. Immunol. 21, 23-29 (2009).
38. G. Leroux-Roels, Unmet needs in modern vaccinology: Adjuvants to improve the immune response. Vaccine 28, (Suppl 3), C25-C36 (2010).
39. O. Levy, Innate immunity of the newborn: Basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379-390 (2007).
40. V. J. Philbin, O. Levy, Developmental biology of the innate immune response: Implications for neonatal and infant vaccine development. Pediatr. Res. 65 (suppl.), 98R-105R (2009).
41. P. Méndez-Samperio, L. Belmont, E. Miranda, Mycobacterium bovis BCG Toll-like receptors 2 and 4 cooperation increases the innate epithelial immune response. Arch. Med. Res. 39, 33-39 (2008).
42. E. Latz, J. Franko, D. T. Golenbock, J. R. Schreiber, Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity. J. Immunol. 172, 2431-2438 (2004).
43. B. Adkins, C. Leclerc, S. Marshall-Clarke, Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553-564 (2004).
44. C. B. Wilson, T. R. Kollmann, Induction of antigen-specific immunity in human neonates and infants. Nestle Nutr. Workshop Ser. Pediatr. Program. 61, 183-195 (2008).
45. J. L. Wynn, O. Levy, Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin. Perinatol. 37, 307-337 (2010).
46. D. Baxter, Vaccine responsiveness in premature infants. Hum. Vaccin. 6, 506-511 (2010).
47. S. Saito, Cytokine network at the feto-maternal interface. J. Reprod. Immunol. 47, 87-103 (2000).
48. B. Morein, G. Blomqvist, K. Hu, Immune responsiveness in the neonatal period. J. Comp. Pathol. 137 (suppl. 1), S27-S31 (2007).
49. I. Jónsdóttir, Maturation of mucosal immune responses and influence of maternal antibodies. J. Comp. Pathol. 137, (Suppl 1), S20-S26 (2007).
50. O. Levy, M. Coughlin, B. N. Cronstein, R. M. Roy, A. Desai, M. R. Wessels, The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J. Immunol. 177, 1956-1966 (2006).
51. T. Strunk, D. Doherty, P. Richmond, K. Simmer, A. Charles, O. Levy, K. Liyanage, T. Smith, A. Currie, D. Burgner, Reduced levels of antimicrobial proteins and peptides in human cord blood plasma. Arch. Dis. Child. Fetal Neonatal Ed. 94, F230-F231 (2009).
52. B. P. Morgan, K. J. Marchbank, M. P. Longhi, C. L. Harris, A. M. Gallimore, Complement: Central to innate immunity and bridging to adaptive responses. Immunol. Lett. 97, 171-179 (2005).
53. T. R. Kollmann, J. Crabtree, A. Rein-Weston, D. Blimkie, F. Thommai, X. Y. Wang, P. M. Lavoie, J. Furlong, E. S. Fortuno, 3rd, A. M. Hajjar, N. R. Hawkins, S. G. Self, C. B. Wilson, Neonatal innate TLR-mediated responses are distinct from those of adults. J. Immunol. 183, 7150-7160 (2009).
54. D. F. Angelone, M. R. Wessels, M. Coughlin, E. E. Suter, P. Valentini, L. A. Kalish, O. Levy, Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-alpha production in vitro and in vivo. Pediatr. Res. 60, 205-209 (2006).
55. M. E. Belderbos, G. M. van Bleek, O. Levy, M. O. Blanken, M. L. Houben, L. Schuijff, J. L. Kimpen, L. Bont, Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: Low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin. Immunol. 133, 228-237 (2009).
56. O. Levy, E. E. Suter, R. L. Miller, M. R. Wessels, Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells. Blood 108, 1284-1290 (2006).
57. S. Burl, J. Townend, J. Njie-Jobe, M. Cox, U. J. Adetifa, E. Touray, V. J. Philbin, C. Mancuso, B. Kampmann, H. Whittle, A. Jaye, K. L. Flanagan, O. Levy, Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. PLoS ONE 6, e18185 (2011).
58. J. E. Mold, S. Venkatasubrahmanyam, T. D. Burt, J. Michaëlsson, J. M. Rivera, S. A. Galkina, K. Weinberg, C. A. Stoddart, J. M. McCune, Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695-1699 (2010).
59. M. A. Fernandez, F. K. Puttur, Y. M. Wang, W. Howden, S. I. Alexander, C. A. Jones, T regulatory cells contribute to the attenuated primary CD8+ and CD4+ T cell responses to herpes simplex virus type 2 in neonatal mice. J. Immunol. 180, 1556-1564 (2008).
60. M. A. Avanzini, R. Maccario, C. Belloni, G. Carrera, A. Bertaina, M. Cagliuso, M. La Rocca, C. Valsecchi, M. Mantelli, A. M. Castellazzi, I. Quinti, A. De Silvestri, M. Marconi, B lymphocyte subsets and their functional activity in the early months of life. Int. J. Immunopathol. Pharmacol. 23, 247-254 (2010).
61. J. V. Williams, J. H. Weitkamp, D. L. Blum, B. J. LaFleur, J. E. Crowe, Jr., The human neonatal B cell response to respiratory syncytial virus uses a biased antibody variable gene repertoire that lacks somatic mutations. Mol. Immunol. 47, 407-414 (2009).
62. D. A. Randolph, The neonatal adaptive immune system. Neoreviews 6, e454-e462 (2005).
63. M. PrabhuDas, B. Adkins, H. Gans, C. King, O. Levy, O. Ramilo, C. A. Siegrist, Challenges in infant immunity: implications for responses to infection and vaccines. Nat. Immunol. 12, 189-194 (2011).
64. P. G. Holt, Functionally mature virus-specific CD8(+) T memory cells in congenitally infected newborns: proof of principle for neonatal vaccination? J. Clin. Invest. 111, 1645-1647 (2003).
65. A smarter jab: Big drugs companies see a bright future for vaccines. The Economist (14 October 2010), http://www.economist.com/node/17258858.
66. J. Mestas, C. C. Hughes, Of mice and not men: Differences between mouse and human immunology. J. Immunol. 172, 2731-2738 (2004).
67. C. A. Siegrist, The challenges of vaccine responses in early life: Selected examples. J. Comp. Pathol. 137 (suppl. 1), S4-S9 (2007).
68. R. G. Higbee, A. M. Byers, V. Dhir, D. Drake, H. G. Fahlenkamp, J. Gangur, A. Kachurin, O. Kachurina, D. Leistritz, Y. Ma, R. Mehta, E. Mishkin, J. Moser, L. Mosquera, M. Nguyen, R. Parkhill, S. Pawar, L. Poisson, G. Sanchez-Schmitz, B. Schanen, I. Singh, H. Song, T. Tapia, W. Warren, V. Wittman, An immunologic model for rapid vaccine assessment - A clinical trial in a test tube. Altern. Lab. Anim. 37, (Suppl 1), 19-27 (2009).
69. B. Pulendran, Learning immunology from the yellow fever vaccine: Innate immunity to systems vaccinology. Nat. Rev. Immunol. 9, 741-747 (2009).
70. B. A. Reikie, K. K. Smolen, E. S. Fortuno, 3rd, D. I. Loeffler, B. Cai, D. Blimkie, T. R. Kollmann, A single immunization near birth elicits immediate and lifelong protective immunity. Vaccine 29, 83-90 (2010).
71. B. P. Mahon, The rational design of vaccine adjuvants for mucosal and neonatal immunization. Curr. Med. Chem. 8, 1057-1075 (2001).
72. J. I. Santos, A. Martin, T. De Leon, L. Rivera, M. E. Gaitán, C. Del Rio, G. Oselka, Y. Cervantes, P. Rubio, S. A. Clemens, J. S. de Mendonça, DTPw-HB and Hib primary and booster vaccination: Combined versus separate administration to Latin American children. Vaccine 20, 1887-1893 (2002).
73. K. K. Smolen, D. I. Loeffler, B. A. Reikie, L. Aplin, B. Cai, E. S. Fortuno, 3rd, T. R. Kollmann, Neonatal immunization with Listeria monocytogenes induces T cells with an adult-like avidity, sensitivity, and TCR-Vbeta repertoire, and does not adversely impact the response to boosting. Vaccine 28, 235-242 (2009).
74. A. Bot, C. Bona, Genetic immunization of neonates. Microbes Infect. 4, 511-520 (2002).
75. B. Pulendran, S. Li, H. I. Nakaya, Systems vaccinology. Immunity 33, 516-529 (2010).
76. T. Strunk, A. Currie, P. Richmond, K. Simmer, D. Burgner, Innate immunity in human newborn infants: Prematurity means more than immaturity. J. Matern. Fetal Neonatal Med. 24, 25-31 (2011).
77. K. Van Herck, P. Van Damme, Benefits of early hepatitis B immunization programs for newborns and infants. Pediatr. Infect. Dis. J. 27, 861-869 (2008).
78. R. W. Sutter, T. J. John, H. Jain, S. Agarkhedkar, P. V. Ramanan, H. Verma, J. Deshpande, A. P. Singh, M. Sreevatsava, P. Malankar, A. Burton, A. Chatterjee, H. Jafari, R. B. Aylward, Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: A randomised, double-blind, controlled trial. Lancet 376, 1682-1688 (2010).
79. N. Wood, P. McIntyre, H. Marshall, D. Roberton, Acellular pertussis vaccine at birth and one month induces antibody responses by two months of age. Pediatr. Infect. Dis. J. 29, 209-215 (2010).
80. S. Kurikka, H. Käyhty, H. Peltola, L. Saarinen, J. Eskola, P. H. Mäkelä, Neonatal immunization: response to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine. Pediatrics 95, 815-822 (1995).
81. S. T. Agnandji, K. P. Asante, J. Lyimo, J. Vekemans, S. S. Soulanoudjingar, R. Owusu, M. Shomari, A. Leach, J. Fernandes, D. Dosoo, M. Chikawe, S. Issifou, K. Osei-Kwakye, M. Lievens, M. Paricek, S. Apanga, G. Mwangoka, B. Okissi, E. Kwara, R. Minja, J. Lange, O. Boahen, K. Kayan, G. Adjei, D. Chandramohan, E. Jongert, M. A. Demoitié, M. C. Dubois, T. Carter, P. Vansadia, T. Villafana, M. Sillman, B. Savarese, D. Lapierre, W. R. Ballou, B. Greenwood, M. Tanner, J. Cohen, P. G. Kremsner, B. Lell, S. Owusu-Agyei, S. Abdulla, Evaluation of the safety and immunogenicity of the RTS,S/AS01E malaria candidate vaccine when integrated in the expanded program of immunization. J. Infect. Dis. 202, 1076-1087 (2010).
82. C. M. Galindo, C. J. Acosta, D. Schellenberg, J. J. Aponte, A. Roca, A. Oettli, H. Urassa, J. Armstrong Schellenberg, E. Kahigwa, C. Ascaso, H. Mshinda, F. Lwilla, J. Vidal, C. Menendez, M. Tanner, P. L. Alonso, Humoral immune responses during a malaria vaccine trial in Tanzanian infants. Parasite Immunol. 22, 437-443 (2000).
83. Acknowledgments: The authors acknowledge the mentorship and support of M. Wessels, R. Malley, R. Geha, E. Guinan, and G. Fleisher. The authors also acknowledge the advice and support of G. vanden Bossche and C. Wilson of the Bill & Melinda Gates Foundation. Funding: O.L. received a Bill & Melinda Gates Foundation Grand Challenges Explorations Award and is currently funded by NIH NIAIAD RO1 AI067353-01A1, American Recovery and Reinvestment Act NIH Administrative Supplement 3R01AI067353-05S1, and by Global Health Grant OPPGH5284 from The Bill & Melinda Gates Foundation. Competing interests: O.L. has also received reagent and/or sponsored research support from 3M Drug Delivery Systems and VentiRx, companies that develop TLR agonists as immunomodulatory agents. O.L. is named as an inventor on a patent application for use of certain TLR agonists as neonatal vaccine adjuvants.