April 7, 2011 | 3
Today is January 28, and Lenina has a smashing headache; she is a Streptococcus pneumoniae researcher. Not that this was the main reason for the headache, but an important meeting was being held today to launch the Pneumococcal Molecular Epidemiology Network’s [PMEN] new paper in Science. Oddly enough, her role at the meeting is to summarize the history of Streptococcus pneumoniae prior to her group’s latest bit of information. The meeting would cover the history and evolution of Streptococcus pneumoniae, in general, and the 40 year history of the PMEN-1 clone, specifically. History. The summary was sitting on her desk at work, in the laboratory.
When Lenina was first forced to rethink vaccination in her newer world she had to get over the fact that infants [not embryos] and the elderly [old people?] were targeted. However, "Sterilization is civilization" remained her mantra throughout both worlds. All infectious diseases should just go away; certainly there was a way to either annihilate or prevent them. Sometimes she would be so distraught at work that she would repeat unintelligible nursery rhymes. Her co-workers find her smart, but a little strange most of the time.
Her past belief in being able to control all variables, including microbes, fissured when the illusion of Ford and her world ended after John’s tragic death. She drifted and landed in a contributing laboratory for the Pneumococcal Molecular Epidemiology Network. One can only guess that this was her true destiny…as pneumatic as she was, or used to be. Streptocock P, as she lovingly refers to it, is her life now. Typhoid and sleeping sickness [trypanosomiasis] continue to enter her dreams—she is still a product of her past. However, she stares at the black and white picture in her kitchen, above her sink. Under certain selective pressures she had changed. This Streptococcus pneumoniae has changed, too.
Streptococcus pneumoniae was discovered in the late 1800’s; way before Lenina’s time in her old Brave New World (ca. 2540). It gave her pause. If the immune system allows carriage, it can either remain in the nares or invade the tissues and cause disease [noninvasive, like sinusitis or acute otitis media; or invasive like pneumonia, meningitis, or bacteremia]. Immunity against Streptococcus pneumoniae can either decrease the carriage rate or decrease the likelihood of disease in the vaccinated person. Before adequate vaccination, and as is currently seen in many developing countries, as much as 70% of invasive pneumococcal disease occurred in children less than 2 years of age. It also became the leading cause of meningitis after institution of Haemophilus influenzae type b [Hib] immunization. Acute otitis media is mainly caused by Streptococcus pneumoniae, and although not initially dangerous, it is painful and sequelae can be severe [deafness, meningitis].
Early in the 20th century, rudimentary attempts at pneumococcal vaccination, following the discovery of the outer polysaccharide capsule of Streptococcus pneumoniae, were fairly successful. This early vaccine prevented disease in African miners [who were at high risk for pneumonia], an epidemic of Streptococcus pneumoniae in Massachusetts, and was also used during WWII. This sugar capsule helps the pneumococcus secure itself to intranasal passageways and evade immune responses. Lenina thought about how Gaidos and Weinberger describe the interactions of immune system with pathogen, a very complex series of interactions.
But there was no time to expand on those ideas, because something was more pressing to discuss at the meeting. Pressure. Selective pressure. Another structure on the cell wall of the pneumococcus, the penicillin-binding protein [PBP], was a key element to penicillin’s action against Streptococcus pneumoniae. Penicillin binds to the PBP and causes microbial cell rupture. Not knowing how penicillin worked, but knowing that it saved lives, it was used for infections during WWII and beyond. With penicillin being so effective, researchers lost interest in the vaccine. Selective pressure, however, was beginning to "encourage" Streptococcus pneumoniae to change its PBP just enough to resist the effects of penicillin. By altering its penicillin-binding protein it could increase the concentration of penicillin and other beta-lactam antibiotics needed to kill it. It would resist death, an admirable quality in Lenina’s mind. But the people!
As penicillin became less effective and new knowledge of capsule serotypes [factors that differentiate variant members of same species] came about, development of Streptococcus pneumoniae vaccine restarted. The most common capsular serotypes today are 1, 2, 3, 4, 5, 6A, 6B, 7F, 9V, 12A, 12F, 14, 18C, 19A, 19F, and 23F. The 1977 version of the polysaccharide vaccine contained 13 serotypes, but not enough to prevent disease adequately. In 1983, 23 serotypes were included, but it still didn’t prevent nasal carriage and disease well in children less than 2 years of age. The emergence of drug resistance in many of the serotypes [mainly 6B, 14, 19F and 23F] was also alarming. A better vaccine was needed.
A fairly simple lesson was learned by other vaccines [i.e., Hib] and then applied to Streptococcus pneumoniae vaccine—joining or conjugating the polysaccharide with a protein to increase immunogenicity. By joining the polysaccharide capsule [of serotypes 4, 6B, 9V, 14, 18C, 19F, 23F] with diphtheria toxin [CRM197], the immunogenicity increased in children; and disease decreased by 97%. "Holy Ford!" thought Lenina. This evidence made her tingle. There may be some cross-reactivity or effectiveness with other serotypes not included in the vaccine, but it is obviously not complete as evidenced by the increase of serotype 19A [and others] causing disease. As other serotypes appeared to emerge, they were added to the vaccine. The protein-conjugate vaccine now has 13 different [13-valent] serotypes [1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F]. How many could be added until the body stopped forming immunity from them? It just isn’t known. Lenina has been chasing serotypes in the lab with as much fervor as she would a repulsive yet alluring savage; if only it ends better.
By now Lenina’s coffee is cold and she realizes it’s time to head to the lab for the meeting. Barry would be presenting Dr. Croucher’s data on the PMEN-1 clone. Barry reminds her of John, in the way that he’ll quote Shakespeare while holding the micropipette close to his gels. She places her wide belt over her long blue sweater, the finishing touch. Finishing. After the conjugated vaccine showed such promise, we thought we’d be finished with Streptococcus pneumoniae. Lenina shakes her head. Selective pressure enters into the vaccine field as well.
With everyone gathered around the conference table, all up-to-date on the history, Lenina slumps in her chair, exhausted. "Please pass the coffee," she settles in for the bad news. What researchers and Lenina have found out is that as one population of organisms such as serotype 19F decrease or is wiped out, others fill the void. This type of phenomenon happens when broad-spectrum antibiotics are used. The "bad" bacteria in the gastrointestinal tract, not wiped out by the antibiotic, overgrows because the killed "good" bacteria [commensals] are not around to suppress them. Diarrhea ensues.
The 7-valent protein conjugate vaccine leads to decreased carriage of its serotypes, but it appears that other serotypes possibly more infectious or resistant could take its place. Serotypes not covered by the vaccine have increased and can within a year change—the selective pressure of vaccine. These changes occurred in the US after introduction of the 7-valent vaccine in 2000. PMEN-1, their clone of note, with an original serotype of 23F and multiple antibiotic resistance patterns has changed over time into different serotypes [19F, 19A, 6A, 3, 15B] with even more various resistance patterns. Serotype 19A is becoming a concern in the US, Spain, and Canada. Overall, the vaccine serotypes have decreased, but others that existed previously, but nearly undetected due to small numbers, have moved in to fill the gap [i.e., 19A]. Additionally, what if other organisms such as methicillin-resistant Staphylococcus aureus [MRSA] or worse took its place?
Lenina shifted in her seat, a little too warm in her sweater. The promiscuity of bacteria upset her. This Streptococcus was able to not only change when creating offspring [vertical mutation] but could swap large pieces of its DNA with other organisms [not always with bacteria, horizontal transformation]. These changes could lead to different serotypes with various drug resistance patterns…it was all so messy. It might also lead, someday, to highly resistant mutants much like methicillin-resistant Staphylococcus aureus [MRSA] or vancomycin-resistant Enterococcus [VRE], or the dreaded NMD-1. That would be disastrous. Good thing her Network sorted out 40 years of data, and along with other laboratories, would track bacterial DNA changes to better predict what vaccines are needed.
Lenina hated the thought of a vaccine not working. Perhaps keeping on top of the emerging serotypes was the way to go. But others like Moffit are trying to come up with vaccines that better prime the immune system to fight off all Streptococcus pneumoniae regardless of capsule serotypes and antibiotic resistant patterns. Would that lessen selective pressure? Would she still be tracking serotypes? Time will tell. She has become more comfortable with the unknown, and more flexible.
What she really worries about now, though, are all the children that don’t receive vaccinations. Hundreds of thousands of children in developing countries die each year because getting vaccinations to them has been hindered, not by the parents, but by other factors beyond their control. In Lenina’s country, some parents choose not to vaccinate their children. This, in some places, has decreased herd immunity—lack of spread of disease seen when vaccination rates are over a certain percentage [has geographical variation depending on coverage and efficacy of vaccine]. When an outbreak arises and with the increase of more resistant serotypes, what will happen? These organisms could be more difficult to treat. Already, we are seeing more carriage and disease with resistant strains in both vaccinated and unvaccinated children in daycare centers. In addition, vancomycin, the last hold-out for resistant strains of Streptococcus pneumoniae, may be losing some effect [in vitro tolerance studies]. It’s just a matter of time until it becomes perhaps, a major clinical issue. Perhaps vaccination should become mandatory? After all, Lenina is accustomed to authority.
As Lenina flops down on the couch after her long day, she thinks about the children, and old people, and John; and how back in the old world, she would need soma to numb her. She now lives less with black and white answers, and has learned to enjoy variety and color. A surge of excitement propels her to her closet. She finds an old favorite watercolor. It reminds her of past work at the hatchling laboratory. With a drill, hammer, and a nail, she places it on her living room wall, near the overloaded bookcase. In a nostalgic-like trance she stares at images of her past life’s work. She’s excited about the new work ahead of her, and she knows that absolute control is not possible, nor necessary, and rejoices—with a refreshing beverage.
NOTE: Later, on 4/4/11 Lenina got one of her wishes. The Democratic Republic of the Congo, with help by the GAVI Alliance, the WHO, UNICEF, and the Bill and Melinda Gates Foundation added pneumococcal vaccine to its national vaccination program. Other countries to have recently added Streptococcus pneumoniae vaccine to their programs are Nicaragua, Guyana, Yemen, Kenya, Sierra Leone, and Mali. GAVI’s goal is to add 19 more countries by 2012 and with sufficient funding 40 more countries by 2015.
 Microscopic photograph of Streptococcus pneumoniae; NIH image found on Wikipedia; creative commons attribution license
 Structure of Streptococcus pneumoniae showing polysaccharide capsule and penicillin-binding protein; http://www.brown.edu/Courses/Bio_160/Projects2005/meningitis/vaccines.htm
 Proportion of invasive pneumococcal disease [IPD] in young children due to most common serotypes globally; Johnson et al; PLoS Med. 2010 October; 7:e1000348; creative commons attribution license
 Portion of a watercolor showing typhoid and trypanosome-like images by Artologica; used with permission
 and  Portion of a watercolor showing bacteria and virus-like images by Artologica; used with permission:
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About the Author: CM Doran is a clinical pharmacist [Pharm. D.] with post-doctoral fellowship training in research of infectious disease. She left her post of Assistant Professor at University of Wisconsin’s School of Pharmacy 13 years ago to raise 5 kids with her husband. In her spare time, she works at a local independent pharmacy; reviews books for the New York Journal of Books; and exhibits her love of infectious diseases, literature and the arts on The Febrile Muse [twitters @thefebrilemuse]. Her blog is in its first year, and this is her first appearance on Scientific American’s Guest Blog.
The views expressed are those of the author and are not necessarily those of Scientific American.