Vaccine for Middle Ear Infections: Imitation is the Highest Form of Flattery, Safer Too
Parents of infants and toddlers have become accustomed to recognizing the signs and symptoms of otitis media (OM) - irritability, tugging at ears, loss of appetite, loss of sleep, pain, or fever. In fact, OM, an infection or inflammation of the middle ear, is the most common reason for a sick infant to visit a doctor. OM is also one of the most significant health problems for children in the United States, costing approximately $5 billion annually. OM begins when a viral or bacterial infection spreads from the throat to the middle ear. Viruses and bacteria can cause OM. The three main bacterial causes of otitis media, responsible for roughly equal numbers of cases, are Streptococcus pneumoniae, Moraxella catarrhalis, and Nontypeable Haemophilus influenzae (NTHi). Because of the substantial health burden associated with OM, the NIDCD initiated an intramural research program in the early 1990s to explore strategies in developing a vaccine against the microbes that cause otitis media.
Conventional vaccines are made by injecting an individual with either some or all of the bacterium or virus (called the antigen) to stimulate the production of antibodies against that specific bacterium or virus. The antibodies produced in response to the vaccine bind to the antigen, rendering it harmless. The specific proteins that make up the antibody-binding site are called epitopes. NIDCD intramural scientists developed a detoxified NTHi conjugate vaccine against NTHi. This particular vaccine proved to be both safe and effective in animal models and then in a 2002 Phase I clinical trial involving 40 normal human adult volunteers. In conjunction, NIDCD intramural scientists have also been working on a candidate vaccine for another cause of OM, Moraxella catarrhalis. Pre-clinical testing in animal models with vaccines for Moraxella catarrhalis demonstrated that the vaccines were safe and effective, eliciting a significant immune response that inhibited bacterial growth. However, in the early 1980's, a scientist discovered a way to identify proteins that mimic the natural epitopes. The scientist coined these synthetic proteins "mimotopes.” The mimotopes behave in a manner that is similar to epitopes to produce an immune response, but do not possess the harmful substances that can result in toxicity. In 2003, NIDCD intramural scientists turned to these state-of-the-art molecular biology techniques introduced decades ago, to create a candidate vaccine using mimotopes. The mimotopes were of a sugar-based component found on the surface of NTHi called lipooligosaccharide (LOS).
In hopes of making a more cost-effective, more stable, and safer NTHi vaccine, NIDCD intramural scientists replaced the natural epitopes of LOS with the synthetic mimotopes, reducing the likelihood that the vaccine might have toxic side-effects. The mimotopes not only immunologically mimic LOS from NTHi but will also bind to antibodies specific for NTHi LOS. Preliminary experiments showed that the mimic peptides attached to a carrier were as effective as the natural LOS-based vaccine in significantly decreasing the risk of disease in an animal model. Thus, the identified mimotope peptides are promising candidates for developing another novel vaccine for NTHi.
These studies are significant advances toward the long-term goal of developing a combined vaccine that reduces the incidence of OM caused by all major bacterial pathogens in children. Additional clinical research must be completed to ensure their effectiveness and safety. Vaccine-mediated prevention of OM is particularly important because repeated use of antibiotics to treat otitis media often produces drug-resistant bacterial strains.
Dr. Gu is a Staff Scientist in the Vaccine Research Section at NIDCD.
*Hou Y, Gu XX., Development of Peptide Mimotopes of Lipooligosaccharide from Nontypeable Haemophilus Influenzae as Vaccine Candidates. J Immun 170: 4373-4379, 2003.