Streptococcus pneumoniae is a type of bacterium that commonly inhabits the nasal passages of healthy people, especially children. On occasion, the bacteria will spread from the nasal passages to other parts of the body where it can cause infection and sometimes death.
The most common sites of pneumococcus infection are the
ears (ear infections), lungs (pneumoniae), and brain (one of the most common
forms of bacterial meningitis). Over 90 different serotypes (varieties
of Streptococcus pneumonia) have been identified, based on the types of sugars
that comprise the coating of the bacteria. A good way to think of the different
serotypes of pneumococcus is like a bag of M&Ms with 90 different colors.
Each individual candy has the same chocolate center, but it has a different
colored sugar coating. In the same way, two pneumococci can have a different
sugar coat and yet contain similar constituents inside.
In the United States in the year 2000, the bacterium Streptococcus pneumoniae was responsible for an estimated six million cases of ear infections and over 100,000 hospitalizations for pneumoniae. But since the introduction of the PCV7 vaccine in that same year, the incidence of pneumococcal diseases in the United States has decreased significantly. This breakthrough vaccine targets the seven most common strains of the bacteria, and has been quite effective at preventing pneumococcal infection.
Yet in Africa and South America, over one million children
still die annually from pneumococcal infection. This is because the PCV7 vaccine, which
has been so successful in the United States, has not yet been introduced in
many other parts of the world, and may not cover all the strains that affect
children in other countries. Recent research, however, now offers hope
that in the near future pneumococcal disease may be prevented. Dr. Richard
Malley and his colleagues at Children’s Hospital in Boston have developed a
new vaccine that effectively prevents infections by pneumococcus in mice, regardless
of serotype. They plan to begin human trials soon, and hope that the result
will be a vaccine that can be effective worldwide.
The Challenge
The large variety of bacterial serotypes has made the development of a pneumococcal vaccine difficult because the typical target of bacterial vaccines is often the sugar coat, which varies so much in pneumococcus. One of the most common types of vaccines against bacteria takes the polysaccharide (sugar) coat and chemically attaches this sugar to a protein, in a process called "conjugation". When a child is vaccinated with a "conjugate vaccine", the child makes a much higher level of antibodies to the sugar because it is bound to a protein. The conjugation of the sugar to the protein is thought to trick the immune system of the child into making a stronger response to the sugar as if it were a protein. If an immunized child then encounters a pneumococcal strain that carries that sugar coat, s/he will already have the mechanisms in place to fight off and prevent infection: the antibodies directed against the polysaccharide (the sugar in the coating) will attach to the bacterium and help the child clear it before it can cause disease.
The 2000 PCV7 vaccine was developed against the seven most common serotypes in the United States. In other words, it contains the conjugated polysaccharides from those seven serotypes so that the immunized child will make antibodies against them. If, however, a child is infected with a different bacterium serotype, the child may still develop infection. In February 2010, the Food and Drug Administration approved a similar vaccine that can combat thirteen different serotypes, and thus has the potential to be more broadly effective.
These vaccines were developed to combat the most common
serotypes in the United States, which are not always the most important serotypes
found in other parts of the world, so the vaccine may be less effective in
those places. For a vaccine that would be applicable in all countries, Dr.
Malley and his colleagues developed a technique to create a vaccine that targets
the bacterium itself rather than the sugar coating. In theory this would make
it effective against all serotypes of the bacteria. This type of vaccine is
based on a non-encapsulated (i.e., no sugar coat) pneumococcal strain which
is made into a Whole Cell Vaccine. Dr. Malley and his team introduced several
mutations into the pneumococcus bacteria in order to facilitate vaccine manufacture
and increase the potency of the vaccine.
Dr. Malley and his colleagues then tested the Whole Cell Vaccine for its effectiveness in mice. To do this, they first vaccinated the mice before challenging them with a variety of pneumococcal serotypes. The degree of protection and the immune response of the immunized mice were compared with those of the control mice who were not inoculated. The results from these experiments were extremely positive. The mice immunized with the Whole Cell Vaccine were protected against colonization and infection by every tested serotype while the mice in the control group were not protected.
Needle, Nose, Mouth or Patch?
The next step was to figure out the best method of vaccination. Typically vaccines are given as a needle injection. Dr. Malley and his international team of collaborators (including scientists at a nonprofit research group called PATH, at a vaccine manufacture group in Brazil, and at a university in Sweden) also explored many other routes of vaccination including in the nose, mouth, or via a skin patch. All of these methods worked well, but they are non-traditional ways of developing vaccines. Since such methods may hinder the process of getting approval by the Food and Drug Administration, Dr. Malley and his colleagues decided that the quickest way to evaluate the vaccine in people would be to pursue the more traditional approach using needle injection.
Recently, Dr. Malley’s collaborator Dr. Luciana Leite of Instituto Butantan in Sao Paolo, Brazil, started to produce the vaccine on a large scale. The mass-production of a vaccine must be a very standardized process. The first step is to be able to grow the organism in large quantities in vitro. Once the organism is grown, it must be washed of the medium it was grown in and killed so that it will not harm patients. The killed bacteria are then processed into a vaccine. Under Dr. Leite’s guidance, the Brazilian facility is gearing up to produce enough vaccine for testing it in people through clinical trials.
Clinical trials will be the real test of the effectiveness of the Whole Cell Vaccine. Dr. Malley hopes the vaccine will be shown to be safe and well tolerated in these trials so that it can then go on to be tested for its ability to protect children against pneumococcal infection.
Research With An Additional Benefit — A Second Form of Immunity
Aside from the prospect of creating a universal vaccine, these studies have also provided evidence for a second mechanism which may be important in the development of immunity. For many years it was thought that the only way to develop immunity against this bacterium was to produce antibodies against it. And it is true that producing antibodies against this bacterium is a good way to be protected. However, in developing the Whole Cell Vaccine, Dr. Malley and his colleagues have shown that there is a second form of immunity to this bacterium that is not dependent on antibodies: instead, it is dependent on a particular group of cells called CD4 T cells. The T cells seem to help clear pneumococcal colonization of the nasal passages. It is believed that all pneumococcal infections begin with colonization of the nasal passages, so a vaccine that could prevent or reduce colonization could provide another form of protection: if the child is not colonized, he/she is unlikely to develop disease. In mice, the Whole Cell Vaccine stimulates both antibodies and these particular T cells directed against the pneumococcus, and may trigger a double form of protection against the bacterium.
Arms Length Clinical Trials
When the Whole Cell Vaccine enters clinical trials, Dr. Malley and his team will eagerly follow the results. They will not be directly involved in the clinical testing, however, to ensure objective and unbiased results. At the same time, Dr. Malley plans to continue to research and develop other methods of vaccination, as well as further investigate different types of immunity.
Dr. Richard Malley is an Associate Professor of Pediatrics at Harvard Medical School and a practicing physician in the Division of Infectious Diseases at Children’s Hospital Boston. His laboratory studies the different immune responses to Streptococcus pneumoniae and has developed other vaccine approaches in addition to the whole cell vaccine. Dr. Malley first became interested in science as a kid listening to dinner table conversations about politics and economics in developing countries such as those in Africa and Asia. He decided that such topics were not as interesting to him and turned instead to the sciences. As a medical student, he became interested in infectious diseases and decided to pursue both clinical medicine and research in that area, focusing on children as a pediatrician. One of Dr. Malley’s goals has always been to provide the best possible healthcare for all, which he hopes to do with the development of a potentially universal pneumococcal vaccine. When not in the lab or seeing patients, Dr. Malley enjoys spending time with his family.
For More Information:
Malley, R. 2010. "Antibody and cell-mediated immunity to Streptococcus pneumoniae: implications for vaccine development." Journal of Molecular Medicine, 88: 135-142.
Lu, Ying-Jie, et al. 2010. "GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis." Vaccine, 28: 7468-7475.
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