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Preventing Respiratory Syncytial Virus

Mucosal-based vaccines offer an attractive alternative to needles.

The global vaccine market has been steadily growing over the years and is expected to reach $100 billion by 2025.1

There is currently, however, no effective vaccine against Respiratory Syncytial Virus (RSV), a common and highly contagious virus, which causes serious disease of the lower respiratory tract. RSV represents a major unmet medical need with 64 million new infections world-wide each year and responsible for 250,500 deaths in 2010. While RSV attacks all age groups, the most severe disease occurs in the elderly, patients with chronic lung disease, persons with impaired immunity and very young infants (≤2 years of age), but also children (2-5 years of age).

Furthermore, while challenges clearly remain in the race to develop an effective vaccine against RSV, our scientific understanding of the virus has improved, specifically with the finding that the RSV viral surface F protein is the main target of virus neutralising antibodies. As most potent pathogens bind exclusively to the pre-fusion F protein, the pre-fusion form has emerged as an ideal vaccine candidate.

Some more advanced RSV vaccine candidates rely instead on the less potent post-fusion approach which may not provide optimum protection against infection and disease.  Moreover, unique research conducted by the Imperial College London revealed that nasally secreted antibodies against the F protein correlate better with protection against RSV infection than serum antibodies, but that people do not develop a memory response for such nasal antibodies upon natural infection2, which may explain that people remain susceptible for infection with the same RSV strain during their entire life.

Mucosal Antibodies: First Line of Defense

Currently the majority of vaccines are delivered intramuscularly, including those that protect against pathogens that enter through the body's mucosal linings, such as in the nose. In recent years, scientific knowledge of the mucosal immune system has expanded, increasing opportunities to prevent infection of pathogens that colonize or invade via mucosal surfaces.

Mucous membranes are one of the largest organs of the body, comprising the linings of the respiratory, gastrointestinal and urogenital tracts. They protect parts of the body that are exposed to the external environment. Ninety percent of all pathogens enter the body through a 400-square-meter mucosal lining which employs its own defense mechanisms, making it the body's first line of protection against infection.3

In addition to providing a gateway for critical nutrients, oxygen and other molecules, mucous membranes serve to protect the body from invading pathogens. In fact, mucosal antibodies in the form of immunoglobulin A (IgA) make up 75% of all antibodies in the human body. More IgA is produced in mucosal linings than all other types of antibody combined in the blood; more than five grams are secreted at mucosal surfaces each day. Now the importance of nasally secreted IgA antibodies and the defect in its memory response has been demonstrated for RSV infections, the development of an intranasal RSV vaccine that is able to elicit durable robust anti-F nasal IgA responses in addition to serum antibodies that also may contribute to protection seems to be the logical next step.

Mucosal-based vaccines offer also other attractive benefits over their injectable counterparts. As mucosal vaccines are both non-invasive and needle-free, they provide increased opportunities for vaccine acceptance (particularly among patients who have needle phobias) and safety, avoiding problems of blood borne infections (especially in developing countries), adverse effects such as inflammation at the injection site and problems of interference with existing systemic immunity.2 Moreover, mucosal vaccines may be easier to implement in the already crowded childhood vaccination schedules in which children sometimes already get two different vaccine shots simultaneously in both arms or legs.

SEE ALSO: Anti-Vaccine Movement

Mimicking Mucosal Pathogens

Vaccines administered directly to the mucosa can trigger key localized antibodies and preferentially activate specific cells, leading to a more robust immune response.4 Mucosal vaccines are likely to be most effective when they mimic mucosal pathogens in several key respects including having the ability to adhere to mucosal surfaces, efficiently stimulate innate responses and create immunological "memory" to the target pathogen.5 When antigens are administered with appropriate adjuvants or attenuated live vaccines via mucosal routes (oral, nasal, beneath the tongue, ocular, genital or rectal), the mucosal immune system can trigger even greater systemic and mucosal immune responses.6

At Mucosis, a biotechnology company, we are addressing a significant challenge in vaccine design. The company's approach to vaccine design has the power to induce protective immunity that is natural and comprehensive by stimulating both innate and adaptive immune responses.

The driving force behind this design is Mucosis' proprietary Mimopath® technology, a needle-free, mucosal vaccine platform that uses the safe and established Lactococcus lactis bacterium used extensively in the production of cheese and buttermilk. The non-recombinant bacteria are converted, using a proprietary process, into non-living, non-toxic, bacterium-like particles (BLPs) that can be tethered on its surface with various types of antigens, including those derived from viruses, bacteria, parasites or tumour cells. BLPs created in this manner are suitable for complex multimeric antigens and multiple routes of administration. This unique flexibility provides comprehensive defenses for a range of target populations, such as via intranasal or oral application for children, pregnant women or the elderly population.

From Influenza Virus to RSV

The Mimopath® platform was clinically validated with studies of the company's FluGEM® vaccine that was designed to target the influenza virus. After establishing proof of concept in influenza, Mucosis is now developing additional mucosal vaccines with lead candidate SynGEM® for RSV and are planning to initiate human clinical studies in 2016.

SynGEM® displays the RSV F antigen protein on the Lactococcus BLPs in a unique stable pre-fusion form that displays the most important epitopes with the potential to elicit highly powerful virus neutralising antibodies. The BLP technology allows presentation of stable native trimeric F proteins with the aim to elicit locally secreted IgA in the mucosal layers and a balanced Th1/Th2-type of systemic immune responses that are protective. It will be developed at first instance for the elderly, adults at risk and children, and potentially for pregnant women.

While we don't expect mucosal vaccines to fully replace intramuscular vaccines in the immediate future, we do expect to see more significant disruptions in vaccine development in the coming years. Mucosal vaccines offer several distinct advantages and have demonstrated particularly compelling potential against respiratory diseases, eliciting a strong and robust systemic immune response at the pathogen point of entry. Additionally, we expect to see the use of vaccines continue to evolve in new disease areas (e.g. HIV, Shigella) or to revisit 'old' disease areas (e.g. Pneumonia, HPV, Hepatitis B, measles) as prophylactic or perhaps even as therapeutic agents.

Dr. Kees Leenhouts is a co-founder and Chief Scientific Officer of Mucosis.

References
1. http://who.int/influenza_vaccines_plan/resources/session_10_kaddar.pdf
2. Habibi MS et al. Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus. Am J Respir Crit Care Med. 2015, 191,_1040-1049.
3. Kraehenbuhl JP, Neutra MR. Mucosal vaccines: where do we stand? Curr Top Med Chem. 2013, 13(20), 2609-2628.
4. http://www.path.org/publications/files/TS_update_mucosal_imm.pdf
5. Neutra MR, Kozlowski PA. Mucosal vaccines: the promise and the challenge. Nat Rev Immunol., 2006, 6(2), 148-158.
6. Lycke N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol. 2012,  12(8), 592-605.

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