Lawrence C. Paoletti, Ph.D. Associate Professor of Medicine
Harvard Medical School
Associate Microbiologist, Department of Medicine
The major emphasis of my research has been the development of effective vaccines against group B Streptococcus (GBS). In the past 25 years GBS has persisted as the foremost bacterial cause of sepsis and meningitis among neonates in the United States. It is also responsible for morbidity among peripartum women, the elderly, and those who are immunocompromised. Although antibiotics are effective at preventing and treating GBS infections, the best long-term solution to elimination of GBS disease is with the use of an effective vaccine.
With few exceptions, all GBS strains isolated from humans contain a capsular polysaccharide (CPS). These carbohydrate antigens are important virulence factors and are targets of protective immunity. Nine distinct GBS serotypes have thus far been identified: Ia, Ib, II, III, IV,V, VI, VII, and VIII. In the past, serotypes Ia, Ib, II, and III were equally prevalent in normal vaginal carriage and early onset sepsis (i.e., that developing at less than 7 days of age) in newborns. However, type V GBS has emerged as an important cause of GBS infection in the U.S., and strains of types VI and VIII have become prevalent among Japanese women.
Because GBS vaccines composed of CPS antigens were sub optimally immunogenic in adults, conjugate vaccines were developed by coupling the CPS to immunogenic proteins, a procedure that renders an greater immune response to the CPS. The first conjugate vaccines used oligosaccharides of defined size. Studies with these vaccines described a CPS chain length optimal for eliciting high levels of functional antibody in animals. More recent conjugate vaccines used the entire native CPS structure linked to several sites on the protein. These, like all conjugate vaccines, displayed vastly improved immunogenicity in animals compared to uncoupled CPS.
Successful preclinical results led us to prepare vaccines for use in Phase 1 and 2 clinical trials. Thus far over 650 healthy adults have safely received one or more of six serotype GBS conjugate vaccines. Each serotype conjugate vaccine was well tolerated and elicited a specific immune response. Our goal is to prepare a multivalent GBS conjugate for use as a maternal vaccine for the prevention of neonatal GBS disease. This vaccine may also be implemented for use among non-pregnant adults.
Another field of interest in my laboratory is the physiology of CPS and surface protein expression by GBS. GBS held under defined nutritional conditions produced more CPS at fast as opposed to slow rates of growth. Slower growing cells produced less CPS and were susceptible to complement mediated opsonophagocytosis by human peripheral blood leukocytes. Besides studying mechanisms of pathogenesis, continuous culture of GBS has also been used to optimize the production of CPS for use in conjugate vaccines. The expression of some of the protein antigens important in GBS virulence are also regulated by cell growth rate. This work may lead to a better understanding of the mechanisms of pathogenesis by this important bacterial pathogen.
A new area of research in my laboratory is the design, construction, and testing of vaccines against HIV. The current HIV gp120 subunit vaccine, although immunogenic, does not elicit high levels of viral neutralizing antibodies. Vaccine constructs will hopefully induce greater levels of viral neutralizing antibody.
Paoletti LC, McInnes PM, editors. Vaccines: from concept to clinic. A guide to the development and clinical testing of vaccines for human use. 1999 CRC Press. Boca Raton, Florida.
Paoletti LC. 1999. Considerations in the production of vaccines for use in phase 1 clinical trials and preparation of the manufacturer’s protocol. p. 77-87. In L.C. Paoletti and P.M.McInnes (eds.) Vaccines: from concept to clinic. A guide to the development and clinical testing of vaccines for human use. 1999 CRC Press, Boca Raton.
Baker CJ, Paoletti LC, Wessels MR, Guttormsen H-K, Rench MA, Hickman ME, Kasper DL . Safety and immunogenicity of capsular polysaccharide-tetanus toxoid conjugate vaccines for group B streptococcal types Ia and Ib. J. Infect. Dis. 1999;179:142-150.[abstract]
Paoletti LC, Pinel J, Johnson KD, Reinap B, Ross RA, Kasper DL. Synthesis and preclinical evaluation of glycoconjugate vaccines against group B Streptococcus types VI and VIII. J. Infect. Dis. 1999; 180:892-895.[abstract]
Davies JK, Paoletti LC, McDuffie RS, Madoff LC, Lee S, Eskens J, Gibbs RS. A randomized trial of conjugated Ia group B streptococcal vaccine in a rabbit model of ascending infection. Am. J. Obstet. Gynecol. 1999; 181:803-08.[abstract]
Ross RA, Madoff LC, Paoletti LC. Regulation of cell component production by growth rate in group B Streptococcus. J. Bacteriol. 1999; 181:5389:5394.[abstract]
Paoletti LJ, Bradford J, Paoletti LC. A serotype VIII strain among colonizing group B streptococcal isolates in Boston, Massachusetts. J. Clin. Microbiol. 1999; 37: 3759-3760.[abstract]
Paoletti LC, Madoff LC. Vaccines for the prevention of group B streptococcal disease. UpToDate in Medicine. CD-ROM, 7:3; 1999.
Paoletti LC, Pinel J, Kennedy RC, Kasper DL. Maternal antibody transfer in baboons and mice vaccinated with a group B streptococcal polysaccharide conjugate. J. Infect. Dis. 2000; 181:653-658.[abstract]
Paoletti LC, Madoff LC, and DL Kasper. 2000. Surface structures of group B Streptococcus important in human immunity. p. 137-153. In V.A. Fischetti, R. Novick, J. Ferretti, D. Portnoy, and J. Rood (eds.) Gram positive pathogens. American Society for Microbiology, Washington, D.C.
Baker CJ, Paoletti LC, Wessels MR, Rench MA, Guttormsen H-K, Carey VJ, Hickman ME, Kasper DL. Use of capsular polysaccharide-tetanus toxoid conjugate vaccine for type II group B Streptococcus in healthy women. J Infect Dis. 2000; 182:1129-38.[abstract]
Paoletti LC. 2001. Potency of clinical group B streptococcal conjugate vaccines. Vaccine. 19:2118-2126.[abstract]
Malin G, and Paoletti LC. Use of a dynamic in vitro attachment and invasion system (DIVAS) to determine influence of growth rate on invasion of respiratory epithelial cells by group B Streptococcus. Proc. Natl. Acad. Sci. 2001; 98:13335-13340.[abstract]
Guttormsen H-K, CJ Baker, MH Nahm, Paoletti LC, SM Zughaier, MS Edwards, DL Kasper. Type III group B streptococcal polysaccharide induces antibodies cross-reacting with Streptococcus pneumoniae type 14. 2002. Infect. Immun. 70:1724-1738.[abstract]
Paoletti LC, DL Kasper. Conjugate vaccines against group B Streptococcus type IV and VII. J. Infect. Dis. 2002. 186:123-126.[abstract]
Paoletti LC, RC Kennedy. Neutralizing antibody is induced in mice by novel glycoconjugates of human immunodeficiency virus type 1 gp120 and env2-3. J. Infect. Dis. 2002: 186:1597-1602.[abstract]
Baker CJ, Rench MA, Fernandez M, Paoletti LC, Kasper DL, Edwards MS. Safety and immunogenicity of a bivalent group B streptococcal conjugate vaccine for serotypes II and III. J. Infect. Dis. 2003. 188:66-73.[abstract]
Ferrieri P, Hillier SL, Krohn MA, Paoletti LC, Flores AE. Characterization of vaginal and rectal colonization with multiple serotypes of group B streptococci using multiple colony picks. Indian J. Med. Res. 2004. 119(Suppl):208-212.
Johri AK, Padilla J, Malin G, Paoletti LC. Oxygen regulates invasiveness and virulence of group B Streptococcus. Infect. Immun. 2003. 71:6707-6711.[abstract]
Baker CJ, Paoletti LC, Rench MA, Guttormsen H-K, Edwards MS, DL Kasper. Immune response of healthy women to two different type V group B streptococcal capsular polysaccharide-protein conjugate vaccines. J. Infect. Dis. 2004. 189:1103-1112.[abstract]Mikamo H, Johri AK, Paoletti LC, Madoff LC, AB Onderdonk. Adherence to, invasion by, and cytokine production in response to serotype VIII group B streptococci. Infect. Immun. 2004. 72:4716-4722.[abstract]
Sinha A, Lieu TA, Paoletti LC, Weinstein M, R. Platt. The projected health benefits of maternal group B streptococcal vaccination in the era of chemoprophylaxis. Vaccine. 2005. 23:3187-3195.[abstract]
Johri AK, Patwardhan V, LC Paoletti. Growth rate and oxygen regulate the interactions of group B Streptococcus with polarized epithelial cells. Can. J. Microbiol. 2005. 51:283-286.[abstract]
Maione D, Margarit Y Ros I, Rinaudo D, Masignani V, Mora M, Scarselli M, Tettelin H, Brettoni C, Iacobini ET, Rosini R, D’Agostino N, Miorin L, Buccato S, Mariani M, Galli G, Nogarotto R, Nardi VD, Vegni F, Fraser C, Mancuso G, Teti G, Madoff L, Paoletti L, Rappuoli R, Kasper DL, Telford JL, and G Grandi. Identification of a universal vaccine against group B Streptococcus by screening of the bacterial pan-genome. Science. 2005. 309:148-150. [abstract]
Ramaswamy SV, Ferrieri P, Madoff LC, Flores AE, Kumar N, Tettelin H, Paoletti LC. Identification of novel cps locus polymorphisms in nontypeable group B Streptococcus. J Med Microbiol. 2006 Jun;55(Pt 6):775-83. [abstract]
Ramaswamy SV, Ferrieri P, Flores AE, Paoletti LC. Molecular characterization of nontypeable group B Streptococcus. J Clin Microbiol. 2006 Jul;44(7):2398-403. [abstract]
Madoff LC, Paoletti LC, Kasper DL. 2006. Surface structures of group B Streptococcus important in human immunity. p. 169-184. In V.A. Fischetti R. Novick J, Ferretti D. Portnoy and J.Rood (eds.) Gram positive pathogens. 2nd Edition. American Society for Microbiology, Washington, D.C.
Baker CJ, Rench MA, Paoletti LC, Edwards MS. Dose-response to type V group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine in healthy adults. Vaccine. 2006 Jul 31; [Epub ahead of print]. [abstract]
Johri AK, Paoletti LC, Glaser P, Dua M, Sharma PK, Grandi G, Rappuoli R. Group B Streptococcus: global incidence and vaccine development. Nat Rev Microbiol. 2006 Dec;4(12):932-42. Epub 2006 Nov 6. [abstract]
Johri AK, Margarit I, Broenstrup M, Brettoni C, Hua L, Gygi SP, Telford JL, Grandi G, Paoletti LC. 2007. Transcriptional and proteomic profiles of group B Streptococcus type V reveal potention adherence proteins associated with high-level invasion. Infect Immun. 2007 Mar;75(3):1473-83. Epub 2007 Jan 8. [abstract]
Yang HH, Madoff LC, Guttormsen H-K, Liu Y-D, Paoletti LC. 2007. Recombinant group B streptococcus Beta C protein and a variant with the deletion of its immunoglobulin A-binding site are protective mouse maternal vaccines and effective carriers in conjugate vaccines. Infect Immun. 2007 Jul;75(7):3455-61. Epub 2007 Apr 30. [abstract]
Guttormsen H-K, Paoletti LC, Mansfield KG, Jachymek W, Jennings HJ, Kasper DL. 2008. Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM to IgG switching. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5903-8. Epub 2008 Mar 31. [abstract]
Guttormsen H-K, Liu Y-D, Paoletti LC. 2008. Functional activity of antisera to group B streptococcal conjugate vaccines measured with an opsonophagocytosis assay and HL-60 effector cells. Hum Vaccin. 2008 Sep-Oct;4(5):370-4. Epub 2008 Oct 1. [abstract]
Paoletti LC, Guttormsen H-K, Christian MS, Hoberman AM, McInnes P. 2008. Neither antibody to a group B streptococcal conjugate vaccine nor the vaccine itself is teratogenic in rabbits. Hum Vaccin. 2008 Nov-Dec;4(6):435-43. Epub 2008 Nov 21. [abstract]
Yang H-H, Mascuch S, Madoff LC, Paoletti LC. 2008. Recombinant group B streptococcal alpha-like protein 3 is an effective immunogen and carrier protein. Clin Vaccine Immunol. 2008 Jul;15(7):1035-41. Epub 2008 May 7. [abstract]
Guttormsen H-K, Mascuch SJ, West J, Paoletti LC. 2009. A fluorescence-based opsonophagocytosis assay to measure the functional activity of antibody to group B Strepcoccus. Hum Vaccin. 2009 Jul;5(7):461-6. Epub 2009 Jul 10. [abstract]