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From Polysaccharides to Proteins:
The Challenge of Vaccination against
Serogroup B Meningococcal Disease

Adviser: Adel A. Mahmoud

Danielle H. Rochlin

Molecular Biology

“... remember that your thesis is as much about personal growth as it is about an original academic contribution.”

rochlin-danielle-helena

As an Orange Key tour guide, one of the key stops on my tour of the Princeton campus was Firestone Library. I would stand on the steps of Firestone Plaza and talk not only about the library’s book collection, but also about the hundreds of study carrels in which students worked on the most defining aspect of their Princeton education: the senior thesis. The thesis, I would explain, is a rite of passage at the University that is completed by all A.B. and most B.S.E. candidates, typically ranging from 80 to 100 pages. Some students have expanded upon their theses after graduation; Wendy Kopp ’89, for instance, developed her senior thesis into the Teach for America program. 

After reciting these facts on a weekly basis as an underclassman, I grew nervous when, at the beginning of my junior year, I realized that it was finally my turn to face the thesis. The task seemed daunting at first, especially in light of the impressive theses of Princeton alumni. Looking back at how I felt at that time, after having completed a thesis of my own, I cannot claim that my emotions were entirely misguided; writing a senior thesis is an immense undertaking, but it also is an empowering and enjoyable process.

I have used the word “process” intentionally, since producing a thesis unfolds as a series of stages, beginning with concept development and research, followed by writing and revision (and then more revision!). For me, the process began in the fall of my junior year when I began to search for a thesis adviser and topic compatible with my academic interests. As a student concentrating in molecular biology and earning a certificate in the Woodrow Wilson School of Public and International Affairs, I wanted to write a nonlab thesis that combined elements of basic science and public health, preferably applied on an international level. I was pleased to discover that Professor Adel Mahmoud was well suited to advise me in this area; not only were our general interests aligned but, most importantly, he seemed genuinely excited to enlist me as his advisee. Identifying a specific thesis topic, I soon learned, was a more difficult task than selecting an adviser. As I struggled to select one of the innumerable topics within the realm of global health science, Professor Mahmoud provided a simple yet enduring suggestion: Read journals and newspapers without any preconceptions, observing which topics spark your interest and curiosity. After several weeks of browsing publications ranging from Nature to the New York Times, I found an area of substantial intrigue: the development of a vaccine against Neisseria meningitidis serogroup B (MenB). 

N. meningitidis, commonly referred to as meningococcus, is a bacterium that poses a substantial global health problem, causing meningitis and/or septicemia in infected individuals. The bacterium is present in several serogroups, and while vaccines have been developed to combat most pathogenic strains, there is currently no licensed serogroup B vaccine that is capable of achieving widespread coverage. Vaccines against other serogroups target the capsular polysaccharide (CPS), an outer structure that encapsulates pathogenic meningococci; however, the structural similarity of the serogroup B CPS to an endogenous human macromolecule, combined with the genomic flexibility characteristic of the organism, has thwarted traditional immunization efforts against serogroup B. For my spring junior paper (JP), I outlined a proposal for my thesis: to advance solutions to the design of a universal MenB vaccine, a puzzle that had eluded scientists throughout the past century. 

To reflect my studies of public policy in the Woodrow Wilson School certificate program, I planned to add a chapter at the end of my thesis discussing a policy-based problem concerning N. meningitidis serogroup A (MenA). Unlike MenB, which primarily circulates in developed countries, MenA is a debilitating public health threat in sub-Saharan Africa. Control of MenA in this region is limited by commercial, rather than scientific, difficulties; high risk and a lack of profitability have deterred vaccine manufacturers from developing country markets. For this supplementary thesis chapter, I thus intended to investigate models that could achieve affordable and effective MenA conjugate vaccine development for sub-Saharan Africa. 

During the summer before my senior year, I investigated my proposed thesis topic with funding that I was awarded from the University’s Global Health Scholars Program. I had realized early during the JP process that I would not be able to thoroughly investigate all aspects of my research proposal with a pre-established internship and, with Professor Mahmoud’s assistance, I thus sought to craft a research program tailored to my project. I sent out e-mail requests to several individuals within my proposed field of study in early March; by late June, following extensive e-mail exchanges between myself and contacts at the organizations I wished to visit, I had established a research plan for my August travels. I first spent two weeks at Novartis Vaccines and Diagnostics (Siena, Italy), where a team of researchers had pioneered a genomic method to advance MenB vaccine development. The method, known as reverse vaccinology, identifies vaccine targets through an examination of the complete set of proteins encoded in the pathogen genome, and was used to produce a vaccine in clinical testing. I next visited the United Kingdom Department of Health in London, which had controlled an epidemic of meningococcal meningitis in 1999–2000, followed by the World Health Organization in Geneva, which has teams involved in meningococcal vaccine development and epidemic response. I also interviewed team leaders at the Meningitis Vaccine Project in Ferney-Voltaire, France, an organization aiming to facilitate the development of a MenA conjugate vaccine for use in sub-Saharan Africa.

I arrived back at Princeton to begin the fall semester of my senior year with binders of information that I had collected over the summer, in addition to hours of interviews that I had tape-recorded. With all of this information, I thought that I was prepared to begin writing; however, narrowing down the reams of information I had acquired was a surprisingly difficult task. I spent much of the fall pursuing tangents of my summer research, only to be reminded by Professor Mahmoud that I was straying too far from the core of my topic and needed to narrow my scope. For instance, I was interested in the epidemiology of N. meningitides serogroup C in the United Kingdom, yet this line of investigation fit neither with my molecular research on MenB, nor my inquiry into MenA vaccination in Africa. Ultimately, I decided to treat several aspects of my summer studies as background knowledge, allowing me to “become an expert in one field,” as my adviser would say, rather than superficially knowledgeable in several areas. Collecting my bound thesis from the printer in late April, I felt confident that what I held in my hands thoroughly examined the most pressing scientific and policy-oriented challenges concerning meningococcal disease.

After navigating the process of writing a thesis, I have a few parting pieces of advice for the next generation of Princeton seniors. First, take advantage of the many resources at your disposal. As an institution that emphasizes independent research, Princeton has established substantial facilities and opportunities to advance senior thesis work, ranging from reference librarians to departmental thesis funding, and even subject-specific writing tutors at the Writing Center. Second, establish a thesis schedule, and follow it as you would a course schedule. Time management is key to producing a well-researched, well-written thesis, since beginning early and adhering to self-imposed chapter deadlines can help you to avoid writing and editing crunches as your thesis due date draws near. Finally, and perhaps most importantly, remember that your thesis is as much about personal growth as it is about an original academic contribution. There is no way to deny the intimidating success of theses that have won mention in the script of Orange Key tours. Yet, though I advanced novel suggestions in my area of study, I also developed into a confident and independent scientific thinker while researching and writing my thesis—and that is just as important.

From Polysaccharides to Proteins:
The Challenge of Vaccination against
Serogroup B Meningococcal Disease

Danielle H. Rochlin

Adel A. Mahmoud

Senior Policy Analyst, Woodrow Wilson School
and Molecular Biology and Lecturer with the
Rank of Professor in Molecular Biology

“Danielle returned from these multiple exposures with a wealth of understanding and appreciation of the scientific and policy challenge to discover, develop, and deploy meningitis vaccines.”

Molecular biology majors are offered the opportunity to engage in non-laboratory-based research for their junior paper (JP) and senior thesis. Only a few select numbers of students who are usually interested in broader implications of scientific pursuits chose this unique option. The process for selecting a specific subject for the JP and a faculty supervisor starts toward the end of the fall semester. Following a series of interviews, a matching process is used to pair a student or two with a specific faculty member. Emphasis in the JP is on perceiving and writing a research proposal using National Institutes of Health guidelines for investigator-initiated research. I was fortunate to have Danielle Rochlin choose to work with me on an area that is scientifically challenging and exciting from the policy point of view. Danielle focused her JP on the molecular biology of Neisseria meningitidis and the challenge of developing an effective vaccine against the most clinically and epidemiologically relevant serotypes. Meningococcal meningitis is a major global burden of infectious disease, and it challenges the public health authorities in developed and developing countries. Danielle focused on the challenge of developing vaccines against serotype B, as it has been the most daunting task over the past two decades. Her effort during the spring semester of junior year was remarkable in quality, focus, and depth, and it was a diligent attempt to appreciate the multifaceted nature of the challenge. Danielle’s JP was ranked at the top of all papers submitted by those majoring in molecular biology that year and set the stage for her senior thesis.

There are multiple aspects to the unique “thesis experience” at Princeton. Perhaps the most significant is the University’s ability to support students during summer months between junior and senior years in developing firsthand experience with a specific research subject. Danielle took full advantage of such an opportunity and explored three complementary aspects of the global meningitis challenge. First, she examined in detail the approach of the United Kingdom’s government to introduce a vaccination requirement for adolescents against bacterial meningitis. Then, she studied a model of public-private partnership aiming at producing specific meningitis A vaccine for the meningitis belt in West and Central Africa. Finally, she spent considerable effort working side by side with investigators at Novartis Vaccines and Diagnostics in Siena, Italy, to gain a close look at the theory and practice of reverse vaccinology and its application to produce meningitis B vaccine, which is currently in late-stage testing.

Danielle returned from these multiple exposures with a wealth of understanding and appreciation of the scientific and policy challenge to discover, develop, and deploy meningitis vaccines. This was immediately evident in the way she outlined her approach to tackle the preparation of her senior thesis. The wealth of information, the quality of understanding the molecular and biochemical aspects of N. meningitides, and the depth in approaching analysis and documentation of every chapter in her thesis were phenomenal. I learned from reading drafts of her chapters more than I learned from the standard textbooks and the most recent publications on the subject. Danielle approached working on her senior thesis with serious dedication and disciplined commitment. She was always on time in delivery of her chapters. Danielle’s thesis provided an independent and neutral look at the program in the U.K. and the meningitis vaccine project, as well as a thorough analysis of the antigens chosen for the reverse vaccinology approach. Her emphasis was on scientific evidence based on independent approaches and moving the field forward. This senior thesis was a model of an in-depth, scholarly examination of a complex scientific issue. It is written with commanding knowledge and elegant style. It was no wonder that Danielle collected a lot of the top prizes at graduation.

Danielle’s experience is a model for the opportunities available for Princeton students. The thesis affords an extended period of time to focus on thinking and planning, then generating primary information from relevant sources wherever they happen to be located. The senior thesis fuses these activities by cohesively presenting a systematic examination of the issue, evidence, and recommendations. It is such an opportunity that places this experience at the top of the four years of study and it is uniquely Princetonian!