My Research

First Observation of Protozoa, painting by Robert Them of Antonie Philips van Leeuwenhoek, who by skilled use of microscopy first discovered bacteria protists sperm cells blood cells and many other examples of structures in animal and plant tissues. His research was widely read and opened up new frontiers for scientists to investigate.

My research focuses on the prevention and control of infectious diseases. I was interested in the evolutionary, cellular and molecular basis of infectious disease and pioneered the use of novel epidemiological, immunological and genomics techniques to explore them. In particular I studied Chlamydia trachomatis infections and emerging infectious diseases in great detail. I was interested in Chlamydia because of its effects on reproduction and the importance of immunology to its clinical features. I studied emerging infectious diseases because, as experiments of nature, they reveal how changes in human populations or changes in the genetics of a pathogen allow disease emergence.
 
With C trachomatis I demonstrated the epidemiological importance of infection to women’s reproductive and sexual health (1-6). I developed evidence for a specific cellular and molecular model of C. trachomatis immunology (7). This included proving the central importance of interferon gamma secreting CD4 T cells in chlamydia immunity by studying the epidemiology of chlamydia infection among commercial sex workers in Nairobi Kenya, some of whom had HIV infection (8-14). Because CD4 T cells were central to chlamydia immunity the challenge became identifying chlamydia antigens capable of stimulating such T cells (15). This challenge required two obstacles to be overcome. The first involved determining the genome sequence of Chlamydia muridarum, the laboratory strain used for studying chlamydia immunology. This was completed in partnership with TIGR (16, 17). This was necessary because in principle the genome should include all potential antigens for an organism. After obtaining this knowledge the second challenge was to define those antigens capable of stimulating CD4 T cells. To do this required another experimental innovation, that is the purification of major histocompatibility complex molecules (MHC) from professional antigen presenting cells infected with the pathogen and eluting bound peptides and sequencing peptides with mass spectrometry. This was successfully achieved in partnership with Leonard Foster at UBC (18). The peptides were of interest not on their own but because they identified proteins from chlamydiacapable of entering the antigen processing pathways that allow presentation by MHC class I and II molecules. Proteins that generated class II peptides were found and were demonstrated to confer protection. They have been used to develop a subunit protein vaccine (19-23). Characterization of the chlamydia proteins that preferentially stimulated CD4 T cells showed them to be mainly outer membrane proteins in accordance with what is known generally about protective microbial antigens (24). This basic work stimulated big Pharma to re-launch vaccine development programs for chlamydia. This became even more important when it was found that chlamydia control based on testing and treating was failing to control spread of infection (25). I took a 6-month sabbatical at the Novartis Global Vaccine Centre with Dr Rino Rappuoli to further understand how to catalyze big Pharma interest in vaccine development. I coauthored an essay outlining that a vaccine was clearly needed to control chlamydia (26). For this body of work, I was awarded the Living Legend Award by the Julius Schachter International Symposium on Human Chlamydial Infection in 2022. Because this Award is chosen by fellow scientists it is considered the highest honor in the chlamydia field.
 
While waiting for a chlamydia vaccine I became interested in further improving chlamydia control by existing medical and public health means. I developed mathematical models of sexually transmitted disease transmission after a sabbatical with Dr Roy Anderson which proved influential with public health agencies such as the US CDC in focusing their STD control programs (27). For this contribution I received the Thomas Parran Award by the American Sexually Transmitted Disease Association in 2004 (28). This is the highest honor in the STD public health field.
 
As mentioned earlier I have a long-standing research interest in emerging infectious diseases having studied outbreaks and epidemics of chancroid (29), syphilis (30, 31) and HIV/AIDS (32) over the course of my career at the University of Manitoba. This attracted me in 1999 to become Director of the British Columbia Centre for Disease Control in association with the University of British Columbia. I had experience with infectious disease epidemiology and vaccine development. I had unique insight into the potential impact of genomics and mathematical modelling on responding to infectious disease outbreaks, epidemics and pandemics. I arrived with right skills at the right time to the right place. Using these approaches major impacts were made in responding to SARS, pandemic Influenza, Crytococcus gatti, lymphogranuloma venereum and tuberculosis. The principal impact has been to show how important it is for public health organizations to respond with genomics, rapid vaccine development and molecular epidemiology to emerging infectious diseases. This knowledge proved essential in stemming the catastrophic impact that COVID-19 might have had on global mortality. Thus prior to COVID-19 we demonstrated the unique importance of sequencing outbreak pathogens with SARS (33), influenza (34), Cryptococcus (35) and lymphogranuloma venereum (36). We demonstrated that the genomic approach was useful in tracking the spread of a tuberculosis outbreak (37). This proven essential in tracking the spread of variants of concern with SARSCoV2. In responding to SARS we demonstrated a strategy in rapidly accelerating the development of vaccines called SAVI (the SARS vaccine initiative). In less than two years we produced three vaccine candidates that were suitable for human clinical trials (38-40). Luckily SARS was controlled with existing public health measures and a vaccine was not required. Nonetheless the concept of accelerated vaccine development was key to the development of mRNA vaccines and the control of COVID-19 in under a year. Lastly in responding to SARS we used traditional public health measures of case identification, isolation of cases and quarantining of contacts. To optimally implement these approaches, we developed a highly influential mathematical model which proved useful in deploying similar public health measures to control COVID-19 (41). Because of my achievements in responding to SARS and other emerging infectious disease in 2010 I received the Order of BC.
 
Overall, my research on the prevention and control of Chlamydia trachomatis and emerging infectious diseases has had global impact on the prevention and control of infectious diseases. Many of my publications have become citation classics. Over the long-term the legacy of my research may be how it is influencing other scientists in how they approach their infectious disease research by using novel epidemiological, immunological and genomic methods.
 
  
Bibliography
 
1.         Brunham RC, Paavonen J, Stevens CE, Kiviat N, Kuo CC, Critchlow CW, et al. Mucopurulent cervicitis--the ignored counterpart in women of urethritis in men. N Engl J Med. 1984;311(1):1-6.
2.         Brunham RC, Maclean IW, Binns B, and Peeling RW. Chlamydia trachomatis: its role in tubal infertility. J Infect Dis.1985;152(6):1275-82.
3.         Brunham RC, Binns B, McDowell J, and Paraskevas M. Chlamydia trachomatis infection in women with ectopic pregnancy. Obstet Gynecol. 1986;67(5):722-6.
4.         Brunham RC, Binns B, Guijon F, Danforth D, Kosseim ML, Rand F, et al. Etiology and outcome of acute pelvic inflammatory disease. J Infect Dis. 1988;158(3):510-7.
5.         Brunham RC, Peeling R, Maclean I, Kosseim ML, and Paraskevas M. Chlamydia trachomatis-associated ectopic pregnancy: serologic and histologic correlates. J Infect Dis. 1992;165(6):1076-81.
6.         Brunham RC, Gottlieb SL, and Paavonen J. Pelvic inflammatory disease. N Engl J Med. 2015;372(21):2039-48.
7.         Brunham RC. Problems With Understanding Chlamydia trachomatis Immunology. J Infect Dis. 2022;225(11):2043-9.
8.         Brunham R, Yang C, Maclean I, Kimani J, Maitha G, and Plummer F. Chlamydia trachomatis from individuals in a sexually transmitted disease core group exhibit frequent sequence variation in the major outer membrane protein (omp1) gene. J Clin Invest. 1994;94(1):458-63.
9.         Kimani J, Maclean IW, Bwayo JJ, MacDonald K, Oyugi J, Maitha GM, et al. Risk factors for Chlamydia trachomatis pelvic inflammatory disease among sex workers in Nairobi, Kenya. J Infect Dis. 1996;173(6):1437-44.
10.       Brunham RC, Kimani J, Bwayo J, Maitha G, Maclean I, Yang C, et al. The epidemiology of Chlamydia trachomatis within a sexually transmitted diseases core group. J Infect Dis. 1996;173(4):950-6.
11.       Peeling RW, Kimani J, Plummer F, Maclean I, Cheang M, Bwayo J, et al. Antibody to chlamydial hsp60 predicts an increased risk for chlamydial pelvic inflammatory disease. J Infect Dis. 1997;175(5):1153-8.
12.       Cohen CR, Nguti R, Bukusi EA, Lu H, Shen C, Luo M, et al. Human immunodeficiency virus type 1-infected women exhibit reduced interferon-gamma secretion after Chlamydia trachomatis stimulation of peripheral blood lymphocytes. J Infect Dis. 2000;182(6):1672-7.
13.       Cohen CR, Koochesfahani KM, Meier AS, Shen C, Karunakaran K, Ondondo B, et al. Immunoepidemiologic profile of Chlamydia trachomatis infection: importance of heat-shock protein 60 and interferon- gamma. J Infect Dis.2005;192(4):591-9.
14.       Ondondo BO, Brunham RC, Harrison WG, Kinyari T, Sheth PM, Mugo NR, et al. Frequency and magnitude of Chlamydia trachomatis elementary body- and heat shock protein 60-stimulated interferon gamma responses in peripheral blood mononuclear cells and endometrial biopsy samples from women with high exposure to infection. J Infect Dis. 2009;199(12):1771-9.
15.       Brunham RC, and Rey-Ladino J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat Rev Immunol. 2005;5(2):149-61.
16.       Read TD, Brunham RC, Shen C, Gill SR, Heidelberg JF, White O, et al. Genome sequences of Chlamydia trachomatis MoPn and Chlamydia pneumoniae AR39. Nucleic Acids Res. 2000;28(6):1397-406.
17.       Read TD, Myers GS, Brunham RC, Nelson WC, Paulsen IT, Heidelberg J, et al. Genome sequence of Chlamydophila caviae (Chlamydia psittaci GPIC): examining the role of niche-specific genes in the evolution of the Chlamydiaceae. Nucleic Acids Res. 2003;31(8):2134-47.
18.       Karunakaran KP, Rey-Ladino J, Stoynov N, Berg K, Shen C, Jiang X, et al. Immunoproteomic discovery of novel T cell antigens from the obligate intracellular pathogen Chlamydia. J Immunol. 2008;180(4):2459-65.
19.       Yu H, Jiang X, Shen C, Karunakaran KP, and Brunham RC. Novel Chlamydia muridarum T cell antigens induce protective immunity against lung and genital tract infection in murine models. J Immunol. 2009;182(3):1602-8.
20.       Yu H, Jiang X, Shen C, Karunakaran KP, Jiang J, Rosin NL, et al. Chlamydia muridarum T-cell antigens formulated with the adjuvant DDA/TDB induce immunity against infection that correlates with a high frequency of gamma interferon (IFN-gamma)/tumor necrosis factor alpha and IFN-gamma/interleukin-17 double-positive CD4+ T cells. Infect Immun. 2010;78(5):2272-82.
21.       Yu H, Karunakaran KP, Kelly I, Shen C, Jiang X, Foster LJ, et al. Immunization with live and dead Chlamydia muridarum induces different levels of protective immunity in a murine genital tract model: correlation with MHC class II peptide presentation and multifunctional Th1 cells. J Immunol. 2011;186(6):3615-21.
22.       Yu H, Karunakaran KP, Jiang X, Shen C, Andersen P, and Brunham RC. Chlamydia muridarum T cell antigens and adjuvants that induce protective immunity in mice. Infect Immun. 2012;80(4):1510-8.
23.       Yu H, Karunakaran KP, Jiang X, and Brunham RC. Evaluation of a multisubunit recombinant polymorphic membrane protein and major outer membrane protein T cell vaccine against Chlamydia muridarum genital infection in three strains of mice. Vaccine. 2014;32(36):4672-80.
24.       Karunakaran KP, Yu H, Jiang X, Chan Q, Moon KM, Foster LJ, et al. Outer membrane proteins preferentially load MHC class II peptides: implications for a Chlamydia trachomatis T cell vaccine. Vaccine. 2015;33(18):2159-66.
25.       Brunham RC, Pourbohloul B, Mak S, White R, and Rekart ML. The unexpected impact of a Chlamydia trachomatis infection control program on susceptibility to reinfection. J Infect Dis. 2005;192(10):1836-44.
26.       Brunham RC, and Rappuoli R. Chlamydia trachomatis control requires a vaccine. Vaccine. 2013;31(15):1892-7.
27.       Brunham RC, and Plummer FA. A general model of sexually transmitted disease epidemiology and its implications for control. Med Clin North Am. 1990;74(6):1339-52.
28.       Brunham RC. Parran Award Lecture: insights into the epidemiology of sexually transmitted diseases from Ro = betacD. Sex Transm Dis. 2005;32(12):722-4.
29.       Jessamine PG, and Brunham RC. Rapid control of a chancroid outbreak: implications for Canada. Cmaj.1990;142(10):1081-5.
30.       Lee CB, Brunham RC, Sherman E, and Harding GK. Epidemiology of an outbreak of infectious syphilis in Manitoba. Am J Epidemiol. 1987;125(2):277-83.
31.       Rekart ML, Patrick DM, Chakraborty B, Maginley JJ, Jones HD, Bajdik CD, et al. Targeted mass treatment for syphilis with oral azithromycin. Lancet. 2003;361(9354):313-4.
32.       Cameron DW, Simonsen JN, D'Costa LJ, Ronald AR, Maitha GM, Gakinya MN, et al. Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. Lancet. 1989;2(8660):403-7.
33.       Marra MA, Jones SJ, Astell CR, Holt RA, Brooks-Wilson A, Butterfield YS, et al. The Genome sequence of the SARS-associated coronavirus. Science. 2003;300(5624):1399-404.
34.       Hirst M, Astell CR, Griffith M, Coughlin SM, Moksa M, Zeng T, et al. Novel avian influenza H7N3 strain outbreak, British Columbia. Emerg Infect Dis. 2004;10(12):2192-5.
35.       D'Souza CA, Kronstad JW, Taylor G, Warren R, Yuen M, Hu G, et al. Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts. mBio. 2011;2(1):e00342-10.
36.       Harris SR, Clarke IN, Seth-Smith HM, Solomon AW, Cutcliffe LT, Marsh P, et al. Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing. Nat Genet.2012;44(4):413-9, s1.
37.       Gardy JL, Johnston JC, Ho Sui SJ, Cook VJ, Shah L, Brodkin E, et al. Whole-genome sequencing and social-network analysis of a tuberculosis outbreak. N Engl J Med. 2011;364(8):730-9.
38.       See RH, Zakhartchouk AN, Petric M, Lawrence DJ, Mok CPY, Hogan RJ, et al. Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus. J Gen Virol. 2006;87(Pt 3):641-50.
39.       Zakhartchouk AN, Sharon C, Satkunarajah M, Auperin T, Viswanathan S, Mutwiri G, et al. Immunogenicity of a receptor-binding domain of SARS coronavirus spike protein in mice: implications for a subunit vaccine. Vaccine.2007;25(1):136-43.
40.       See RH, Petric M, Lawrence DJ, Mok CPY, Rowe T, Zitzow LA, et al. Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines. J Gen Virol. 2008;89(Pt 9):2136-46.
41.       Meyers LA, Pourbohloul B, Newman ME, Skowronski DM, and Brunham RC. Network theory and SARS: predicting outbreak diversity. J Theor Biol. 2005;232(1):71-81.
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