Brain Fever

The following sections are included:

• Dedication
• Foreword
• Acknowledgements
• Contents
• Timeline
• Prologue

During my years as a medical student, trainee and ultimately a professor specialising in infections of childhood, caring for children with meningitis was among the most anxiety-provoking and challenging experiences of my professional life. When it first begins, meningitis is often no different from many other illnesses, perhaps seeming no worse than a mild case of “flu.” But as it progresses, fever becomes pronounced accompanied by headache, cold hands and feet, vomiting and aching muscles. Breathing becomes rapid and there may be neck stiffness, dislike of bright light, seizures, altered behaviour and sleepiness. As with my patient Julia, a rash that does not fade may be an ominous warning sign. But these symptoms may happen in any order and some may not happen at all, especially in very young babies in whom recognising meningitis is notoriously difficult…

The most important forms of meningitis are caused by germs called bacteria. Like so many scientific facts, this simple statement turns out to be complicated. Not all germs are bacteria; there are — in order of size (smallest to largest) — viruses, bacteria, fungi and parasites. Collectively, these different germs are often called microbes — extremely small life forms that can only be seen with a microscope. They are widespread in nature and most are beneficial to life. But a minority (called pathogens) are harmful to us because they can cause disease. Over the next two chapters, I’ll tell you about bacteria in general and then about the different kinds (species) of bacteria that cause meningitis…

Books often have heroes and villains, but few have as their central characters tiny single cells, roughly 1.0 μm long and 0.3 μm wide with confusing Latin names: although many different species of bacteria can cause acute (sudden onset) meningitis, three are predominant and are the centrepiece of this book. Their names are a mouthful: Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae. (These are species names, the same nomenclature used to refer to humans as Homo sapiens). I’ll use the shorter, alternative names for these bacteria: pneumococcus, meningococcus and H. influenzae (Hi)…

I had wanted to be a doctor from a young age although it’s hard to discern how and why this resolute commitment happened so early in my life. I recall my parents reading a book entitled A Surgeon Remembers, written by the prolific George Sava, the pseudonym of a British doctor who had been born in Russia. When told I was too young to understand it, of course I was determined to read it. The book consisted of a collection of puzzling medical case studies with a common theme; the answers to what had made the patient ill were not to be found in the textbooks; the doctors were baffled, then Sava intervened and the patient was saved. The notion that you could save a person’s life and be held in awe by your colleagues thrilled and impressed me…

Being a young trainee in the USA in the 1970s was very different from anything I’d experienced in the UK. After medical school, the training of hospital doctors in the UK was largely through work experience; the teaching was loosely structured and junior doctors were so busy that there was little time for dedicated training sessions or further study. In contrast, the residency programme (comprising around 100 trainees) at Boston Children’s Hospital was highly organised with numerous lectures, journal clubs and other supervised training activities. But most striking of all were my fellow junior doctors, including bottom-of-the rung interns many of whom had already been immersed in major, cutting-edge research activities. Several had combined studies for their medical degrees (MDs) with a substantial research project culminating in a PhD, affectionately referred to as “mud-fuds.” I recall having coffee with one as he recounted with pride how a few months earlier he’d given a talk on his research at an international cancer conference. This seemed utterly incredible to me. I was impressed and felt inferior and envious. It was a wake-up call, one of several reasons why, after only a few weeks in Boston, I made up my mind to stay in the US longer than one year. In fact, I was to remain for fourteen…

A few months into my time in Boston in 1970, I decided to seek Janeway’s advice about my future. I was anxious to remain in the US where I was completely caught up in the excitement of a different lifestyle and career opportunities. I entered Janeway’s spacious office where he was seated next to a bay window, his profile silhouetted by the bright light of late afternoon sunshine. It was his habit to see people while at the same time dealing with his voluminous correspondence. I don’t recall much of what I said to him, but I must have rambled on about wanting to do research after my year of residency was completed. For what seemed an age, Janeway was silent. Finally, a few softly spoken words reached me: “Well, I will see what I can do. It is my impression that you are suited to do research if that is what you want”…

My research on an animal model of H. influenzae (Hi) meningitis was a modest part of the larger and more ambitious research agenda to develop a vaccine to prevent Hi type b (Hi-b) meningitis. But the Boston Children’s Hospital scientists were not alone in this quest. Two scientists based at the National Institutes of Health in Bethesda, Maryland — John Robbins and Rachel Schneerson — were also attempting to develop a vaccine, although it was not until the rival groups attended an Annual Paediatric Research meeting in 1972 that each became aware of the other’s work. John Robbins, the son of Jewish immigrants from Brooklyn and a graduate of New York University, had experienced at first hand the impact of Hi-b during his time as a junior doctor working in Florida. Highly intelligent, streetwise and charismatic, John had extraordinary scientific vision. He came across as a domineering, politically incorrect workaholic but someone who showed huge generosity to those around him. His colleague Rachel Schneerson, a Polish-born Jewish immigrant and distant relative of Grand Rebbe Menachem Schneerson, the most prominent Lubavitch rabbi in New York City, complemented Robbins with her hard-nosed, technical brilliance in the laboratory; she was fiercely loyal and dedicated to Robbins’s research…

My fellowship at an end, I left Boston in the summer of 1974 to take up a staff position at Johns Hopkins. After marrying in the autumn of 1973, Marianne and I bought a semi-detached red-brick in the neighbourhood called Guilford, close to the main Johns Hopkins University Homewood campus. Marianne began her graduate training to become a teacher and I took up my post as an assistant professor at Johns Hopkins Hospital, a position in which I was hired to provide expertise in infectious diseases, my major clinical responsibilities being at the affiliated Baltimore City Hospital. The Johns Hopkins Medical Institutions are in the inner city where, in the nineteenth century, newly arrived African Americans made their homes and worked in the city’s shipyards. The later generations populated the inner-city neighbourhoods and, by the 1970s, faced massive unemployment following the economic decline of the docklands and the demise of the Bethlehem Steel Company. The ensuing political and police corruption, violence and drug-dealing were popularised in the HBO cable TV series The Wire. Located in the eastern part of the inner city, the Johns Hopkins Hospital with its lofty dome is a striking landmark, seemingly expressing the aspirations of its thousands of physicians and other health workers. Beneath the dome is a huge statue of Christ fashioned after Thorvaldsen’s original work in Copenhagen. One could not help feeling inspired and privileged to be part of an institution that since the early part of the century had been recognised as the model for all North American medical schools…

As a research fellow in Boston, having excellent research facilities had been something I took for granted. The past year had been a rude awakening; I had struggled because of the inadequate facilities and equipment in my makeshift laboratory at Baltimore City Hospital. Now, thanks to funding from the National Institutes of Health, I had been allocated a generously sized laboratory in the Johns Hopkins Department of Paediatrics. My working days were divided between looking after patients, teaching (medical students and junior doctors) and research. It was a huge privilege to be in a large and prestigious paediatric department consisting of so many brilliant and inspiring colleagues. Their passion and love of medical science left me in no doubt that combining the challenges of work in the hospital wards and clinics with laboratory research was enormously fulfilling. But being a clinician-scientist, a doctor who combines medical practice with laboratory research is a tough challenge. As has been succinctly articulated in a very honest article by one of my contemporaries, “… one quickly finds that basic scientists are sceptical about your scientific knowledge and ability while your clinical colleagues may not regard you as a top-notch clinician, with both groups viewing you with not a little suspicion”…

My life had been a “roller coaster” during 1975–1977 as a result of Marianne’s cancer. My foray into the basic science of bacterial genetics and the joys of fatherhood would make 1978 a special year. Our first child, Christopher, was born in March 1978. It was a scarcely believable and joyful turn around in our lives. On a beautiful early-spring day in April 1978, we drove to see the flowering cherry trees around the Washington Basin by the side of the Potomac. Despite the beauty of the surroundings and the heady emotions of parenthood, I was preoccupied. “I’m thinking about my research” I said to Marianne in a tone of voice she had come to recognise. My mind was in another world — a state that might metaphorically be called Brain Fever. “Just enjoy the magic of the water and the blossom,” Marianne interrupted. Not taking the hint, I started to tell her why the research I was planning to do was so exciting and important to me. It was a blatant example of my addiction to science, a mentality that Marianne has had to cope with throughout our almost 50 years of being married. On this occasion, I think that she would have been more than justified in pushing me into the water, but with her customary patience she let me banter on, not without some scepticism as to what her paediatrician husband was now spending so much time doing; wasn’t my career supposed to be dedicated to looking after sick children?…

In 1979, aged 38, I was made Head of the Division of Paediatric Infectious Diseases at Johns Hopkins. For more than five years, I had had substantial protected time for my research, but this appointment brought about a major transition in my career with greater clinical, teaching and administrative responsibilities. I could no longer devote so much of my own time in the laboratory to progress the research on the work on the type b capsule genetics. The recombinant DNA library had identified just a small part of a larger genetic region (totalling about 1% of the complete genome). Delegating the project proved relatively simple as Susan Hoiseth, who had just completed her PhD in bacterial genetics at Stanford University, had just joined my laboratory. Her flair was apparent immediately and very quickly she made an important discovery. The DNA that I had identified from the genomic library was part of a duplication, a high-frequency genetic switch that resulted in some of the Hi-b bacterial cells ceasing to make the type b capsular polysaccharide. It was puzzling and made no sense to me at the time although Susan thought (correctly as it turned out) that this was a mechanism through which Hi-b could improve its ability to colonise the nose and throat. The Hi-b genetics project was in excellent hands…

“At a recent meeting of the Electoral Board of the University of Oxford for the vacant post of the Professorship of Paediatrics, your name was put forward …” ran the letter that went on to ask if I’d be willing to visit in the near future with a view to being a candidate…

Around 1980, based on the earlier Rockefeller research, Robbins and Schneerson had worked out the required chemical methods to attach the Hi-b capsular polysaccharide to a protein. They used the tetanus toxoid vaccine component as the so-called carrier protein as it was easily available and approved for human use. When laboratory animals were immunised with this conjugate, it drastically improved the quality and quantity of antibodies compared to the polysaccharide alone. Shortly afterwards, Porter Anderson used somewhat different chemistry to couple the Hi-b capsular polysaccharide to a different protein, modified diphtheria toxin, vaccine and obtained antibody responses in baby rabbits that exceeded by 100-fold the amount required to protect against meningitis. In both cases, the reason for this striking improvement of the conjugates, compared to polysaccharide on its own, was the activation of an arm of the immune system known as T-cells that are critical for the efficient induction of antibody responses (see Figure 13.1). Indeed, on the very day (April 1, 1984) that I started my new job in Oxford, scientists at an international meeting in the US reported the results of the first clinical trial of a Hi-b conjugate in infants…

Clinician-scientists lead a somewhat frenetic existence, wearing several hats so that most days are a complex juggling act between taking care of the sick, teaching and research. While orchestrating the Hi-b epidemiology and vaccine trials, my research laboratory was trying to make further progress on the genetics of the type b capsular polysaccharide…

Although I had lived on the east coast of the United States for 14 years, my sabbatical at Washington University, St. Louis, brought home to me how little I knew about the mid-west. A border State between the North and the South, populated by both Union and Confederate sympathisers, Missouri was politically divided during the American Civil war (1861–1865). The horrors of this cataclysmic war in the words of Mark Twain (1873), “… wrought so profoundly upon the entire national character that the influence cannot be measured short of two or three generations.” In 1990, after five generations, the consequences were still resonant…

My sabbatical over, I returned in the summer of 1991 to oversee the trial in which the Hi-b conjugate vaccine was offered to all children in four of eight regions of Oxfordshire. Its outcome was spectacular: there were no Hi-b infections among more than 10,000 immunised children compared to 11 cases in a similar number who had not been given the vaccine. Meantime, the UK Department of Health had put in place a stunningly successful education campaign to prepare for its nationwide introduction. David Salisbury had done his homework, adopting sophisticated marketing strategies. One of the most memorable publicity-clips aired on national television featured an animation of a toddler putting a doll into a coffin. Through these powerful images, parents learned that Hi-b meningitis could be fatal — but importantly, there was a vaccine to prevent this deadly infection…

Centuries ago, folklore and experiences such as the Plague of Athens taught us that once a person has been infected by a microbe, they subsequently resist it much more efficiently through what is called immunity. Vaccines induce immunity by deliberately exposing a person to a harmless form of the germ (or a fragment of it). Although many excellent vaccines are based on weakened (attenuated) versions of the whole infectious organism (for example the viruses of smallpox, measles and polio), there is merit in narrowing down the components to just one, or a very few components (antigens), of a pathogen. Logically, it makes sense that many of the most effective vaccines are based on virulence factors, the microbial components that are directly involved in the disease process, for example, bacterial toxins or the capsular polysaccharides that have been so central to this story. Molecular biology, including methods of cutting (cloning) and pasting (recombining) DNA, provides a means to identify and modify virulence genes (see Chapter 10) that code for proteins that make highly effective vaccines…

I have vivid memories of my first visit to Siena where I fell in love with the city and its stunning surrounding countryside. I recall wandering down Via Franciosa towards Porta Camollia, a triple-arched northern gateway to the centre of the city, with its bas-relief bearing a Medici heraldic shield with the inscription Cor magis tibi sena pandit. The city also provides a physical reminder of the brutal impact of infectious diseases. Its magnificent cathedral remains unfinished, a legacy of the fourteenth-century plague outbreak, the Black Death, from which 60% of Siena’s population perished. Since medieval days, when pilgrims to Rome passed through Siena, visitors pour into the walled city whose cultural legacies continue to be a major tourist attraction. These medieval traditions include the seventeen contrade, each of which lays claim to its own sector of the city. On festival days, members parade — dressed in their distinctive colourful doublets and hose — accompanied by loud drumming. Twice a year, the Piazza del Campo becomes a racecourse as horses and jockeys, representing each of the contrade, compete for the honour of winning Il Palio…

In April 1995, 50 of the world’s leading scientists assembled in the heart of the Cotswolds, for a meeting that would usher in a new epoch in biology. Craig Venter described how the TIGR team had sequenced the thousands of pieces of DNA and used computer programs to assemble the complete bacterial genome of H. influenzae (Hi). As he talked, a large video screen scrolled through the entire sequence, timed to coincide with the length of his talk, a typical piece of Venter showmanship. Here was the genetic information for making 1800 or so proteins that underpinned all the activities required for independent survival and reproduction of a cell. The atmosphere in the meeting room was electric. Many participants hadn’t known or were still sceptical that the DNA sequence of a bacterial genome had been completed. The TIGR scientists had set up several computers in an adjoining room where, after the formal talks were over, participants could inspect the complete genome sequence for themselves. Many were still there in the early hours of the next morning as they identified, often for the first time, the DNA sequences of genes that were crucial to their research. This was also a new way to identify virulence factors and novel targets for treatment or prevention of Hi infection…

In the autumn of 1996, I was asked by Richard Horton, editor of The Lancet, to be the scientific adviser for a series of articles on recent advances in the field of vaccinology. My own contribution was an article in which I discussed how “… complete genome sequences provide a catalogue of the genes for every virulence factor and potential immunogen from which to select vaccine antigens.” This was the first description of what is now a routine approach to developing vaccines — the most recent example being the spike protein of COVID-19…

The success of the MenB vaccine in fighting the appalling New Zealand (NZ) meningitis outbreak (1991–2007) was a huge feather in the cap of Chiron Vaccines. It was also the first step in the plan to develop a universal vaccine, one that would protect against all MenB bacteria, not just the variant that had caused the NZ outbreak. I recall vividly a brainstorming session that Rino Rappuoli organised to set out the strategy and milestones. His relentless energy and brilliance energised the meeting; he took on board all the good ideas while diplomatically steering away from those that were not helpful. He knew exactly what outcome he wanted. It was a master class. The NZ outer membrane vesicle vaccine protected against only 20% of the MenB bacteria that caused meningitis. From the genome sequence, there were data on 28 promising vaccine antigens from which to close the gap on the remaining 80% of isolates. None on their own was sufficient to develop a universal vaccine, but a combination of three genome-derived vaccine proteins, together with the NZ vaccine, gave the best breadth of coverage (see Figure 21.1). This became the basis of the Chiron 4 Component MenB vaccine, 4CMenB…

The development of vaccines against some of the major causes of bacterial meningitis has radically transformed the global picture, although the fight is most certainly not over. But, as I ventured at the beginning of the book, vaccines are the greatest success story of modern medicine and it’s hard to imagine a world without them. Before them, the chance of dying from smallpox was 30% and the lives of survivors were blighted by tell-tale, disfiguring facial pock marks. Look at a dollar bill with its picture of George Washington; the face you see is very different from what people who knew him would recall. In real life, the first American president’s face was pitted and scarred, although the unsightly consequences of smallpox were not always a social disadvantage. Advertisements for servants in the eighteenth century often requested that applicants be pock-marked to ensure they’d been infected, were immune, and therefore couldn’t catch and spread the virus within the household. Thanks to immunisation, smallpox was eliminated from the planet by 1977, the only human disease to have been completely eradicated, but not before it had caused the deaths of hundreds of millions of people…

Given the extraordinary benefits that vaccines have brought to human health, it seems perverse that immunisation is, at least for some, controversial. The problem of vaccine refusal has been identified by the World Health Organisation as one of the top ten threats to global health. The Global Vaccine Alliance (GAVI), an organisation founded in 2000 to facilitate equitable access to vaccines for children from low-income countries, has played a major role in achieving the vaccination of around 760 million children, preventing more than 13 million deaths. Beyond saving lives, vaccines are not just a humanitarian imperative, they are also of profound economic importance and even wealth-creating. So, what has happened to promote the emergence of a widespread and burgeoning mistrust in vaccines? Although concern about the wisdom of getting immunised is not new, it has gathered momentum, especially over the past couple of decades. Interestingly, these fears are more prevalent in socio-economically wealthy countries…

The following sections are included:

• Epilogue
• Glossary