QnAs with Porter W. Anderson, Jr.

The work of National Academy of Sciences (NAS) member Porter W. Anderson, Jr. has benefitted millions of people around the globe: Anderson has spent his career developing vaccines against some of the leading causes of infection in children. For his contributions to the development and commercialization of the Haemophilus influenzae type b (Hib) vaccine—which has virtually eradicated one of the leading causes of meningitis in preschool-aged children—Anderson shared the 1996 Albert Lasker Clinical Medical Research Award with the late David Smith, Rachel Schneerson, and NAS member John Robbins. Since retiring from the University of Rochester in the late 1990s, Anderson has volunteered his time at Children's Hospital in Boston, working with Richard Malley and colleagues on developing inexpensive vaccines against Streptococcus pneumoniae, a common cause of infections in infants.* Here, Anderson discusses their latest pneumococcal vaccines with PNAS.

Porter W. Anderson, Jr.

PNAS: Why have you focused your recent efforts on S. pneumoniae?

Anderson: The bacterium pneumococcus has long been studied by talented scientists but remains a major health problem. It causes nearly 1 million deaths of children per year, mainly in low-income populations. It is efficient in colonizing the human nasopharynx, usually without harm. However, in young children, pneumococcus commonly moves via the eustachian tubes to the middle ear fluid, where it causes earache. When conditions such as a common cold permit it to descend and grow in the lungs, causing pneumonia, pneumococcus resists clearance due to its capsule—a slimy external layer. Its cell wall provokes intense inflammation and fluid accumulation, so the lung becomes ineffective. Although other species of bacteria and viruses also can cause pneumonia, pneumococcus is so-named because of this tendency. Pneumococcus can also invade the bloodstream—causing a dangerous condition called bacteremia, which can lead to sepsis—and the cerebrospinal fluid, causing meningitis, resulting in brain damage or death. Once invasion of lungs, blood, or spinal fluid has begun, treatment with an appropriate antibiotic may fail to prevent death or brain damage. In many areas of the world, access to medical care is limited, resulting in delays in treatment. Also, strains resistant to commonly used antibiotics have evolved.

PNAS: How do your vaccines work?

Anderson: They have a dual action. They stimulate the production of a population of T lymphocytes that, when pneumococcus is encountered, release a protein called interleukin 17A that can activate neutrophils to ingest and kill pneumococcus; and they stimulate the production of antibodies against components common to all types of pneumococcus. The antibody-independent, T lymphocyte mechanism may hasten the clearance of the colonizing bacteria from the nasopharynx. If the bacteria are still able to invade, the antibodies may assist clearance before dangerous numbers arise—a back-up strategy.

PNAS: How are your vaccines different from existing pneumococcal vaccines?

Anderson: The existing vaccines stimulate the production of antibodies specific to the capsules of pneumococcus. However, pneumococci can coat themselves with about 90 differing types of capsule. The existing vaccines, called capsular conjugates, are expensive and cover just a limited number of these types. This approach initially works well but may lose efficacy as the selected types are replaced by nonvaccine types. The two experimental vaccines we describe are directed to noncapsular components of pneumococcus common to all types and are intended for use in infancy. The first of these, consisting of killed whole cells with no capsule, is very inexpensive and could be given by conventional injection or swabbed onto the mucous membranes of the mouth. The second, consisting of three pneumococcal components put together synthetically, is less well developed. In assays in vitro, the killed-cell version has provided immunity against all 17 of the types so far tested.

PNAS: Did your work on the development of the Hib vaccine serve as a model for how to develop these pneumococcal vaccines?

Anderson: No—these are different. Drs. Robbins, Schneerson, Smith, and I developed capsular conjugate vaccines against the Hib bacterium, which has a capsule similar to pneumococcus. Such methods were subsequently used for the capsular conjugates against pneumococcus. When the potential drawbacks of pneumococcal capsular conjugate vaccines became evident, I along with numerous other workers began to look for simpler, more economical alternatives, based on components other than the capsules.

PNAS: You tested early versions of the Hib vaccine on yourself. What compelled you to do this? What did you learn through this experience? Have you also tested your pneumococcal vaccines on yourself?

Anderson: “Going first” was a tradition of medical research still honored when I began in the Hib project. In general, physician-scientists working in an area are best situated to give informed consent to an experimental procedure. David Smith was influential in getting colleagues to volunteer after he and I had been “first.” Also, frequent observations and sample-taking are useful, and this is easier when the subjects are close by. In particular, a challenge with Hib was getting rid of a noxious component of Gram-negative bacteria called endotoxin. At the time, before the horseshoe crab test for endotoxin was available, tiny injections into my own skin was a convenient assay. Fortunately, pneumococcus, like other Gram-positive bacteria, does not make endotoxin.

PNAS: What hurdles need to be overcome for your pneumococcal vaccines to become widely available?

Anderson: The potential for safety and efficacy in infants must be demonstrated—extensive work not possible without the continued support of the health organization PATH and its generous supporters. Then the potential for equivalence or superiority to the existing capsular conjugate vaccines would need to be demonstrated, and it will be challenging ethically to compare an unproven new vaccine with an existing one of known efficacy. PATH has organized a clinical trial of the killed-cell vaccine to begin in February 2012. The three-component synthetic vaccine, spearheaded by our colleague Ying-Jie Lu, is making its way through preclinical trials.

PNAS: What are you planning to do next?

Anderson: I am looking for ways to make the pneumococcus killed-cell vaccine easier to administer. I have helped Ying-Jie Lu a bit in his effort to make a combination vaccine against pneumococcus and typhoid.