Topic: Development of Stable Influenza Vaccine Powder Formulations:
Challenges and Possibilities


Influenza has caused worldwide fear as it affects humans of all race and age. The introductory part of the article states that almost 5-15% of the world population catches influenza every year. Good to know that science has developed an intervention on how to treat the virus and that is by developing an influenza vaccine.

Influenza virus frequently changes their antigens known as antigenic variation that’s why maintaining a successful vaccine is difficult. According to this article, influenza vaccines in liquid form must be stored in a temperature of 2-80C for a span of 1 year only. Since these vaccines can’t withstand heat, the distribution and storage is expensive. On the other hand, heat-stable vaccines are found in the form dry or powdered flu vaccine. Its advantages include better stability and room temperature storage which allows safe stockpiling of the treatment.

Studies show that the nasal route is preferred than parenteral route because stemic and mucosal immune responses are activated. Nasally administered vaccines form a first-line of immune defense for the upper respiratory system, a common entry point for influenza virus, as well as prompting the body's normal systemic immune response.

Developing new pharmacologic methods are highly appreciated because new discovery means improvement.


References:
a. Burton, G.R. & Engelkrik, P. (2004). Microbiology for the Health Sciences (7th ed.). USA: Lippincott Williams and Wilkins

b. Influenza from http://www.brown.edu/Courses/Bio_160/Projects1999/av/influenza.html

c. Maa YF, Ameri M, Shu C, Payne LG, Chen D. Influenza vaccine powder formulation development: spray-freeze-drying and stability evaluation. J Pharm Sci. 2004

Quote: On this study, shows that the nasal route is preferred than parenteral route because systemic and mucosal immune responses are activated.

I did some researches about nasal and parenteral vaccines administration for me to justify if its really true that nasal route is preferred than parenteral route. And two studies came with this result/explanation.

First, According to James Swarbrick, James C. Boylan, vaccination through nasal/mucosal routes provide new avenues for vaccination with a unique advantage of mucosal immunity. Mucosal Immunization presents a realistic alternative to parenteral for inducing protective immune responses. Also the author provides a number of advantages of mucosal/nasal route over parenteral route. These include a) It does not involve hypodermic needles (which I agreed, because it decreases patient's discomfort) b) the total surface of mucosal surfaces in the GIT, respiratory and urogenital tracts where many infectious pathogens come into contact with the host is huge. Thus, preventing infections at the mucosal area provides an immunological first line of defense against diseases. This makes priming of mucosal associated lymphoid tissue (MALT) by vaccination most desirable. Parenteral vaccination alone on the other hand is quite often insufficient in inducing mucosal responses because stimulation of MALT usually requires direct contact between the immunogen and the mucosal surface.

Secondly, In the study of Turker. S. (et.al) discussed that Nasal Administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption.

Having these studies, i can conclude that Nasal Administration is preferrable than Parenteral Administration.

References:

1. Swarbick.J, Boylan J.(2002). Encyclopedia of Pharmaceutical Technology. pp. 2904

http://books.google.com.ph/books?id=knZOYplinRAC&pg=PA2904&lpg=PA2904&dq=vaccines+administration*nasal+route+vs+parenteral+route&source=bl&ots=LX3SJ4Dj9A&sig=FBS-HI5bt_EcQrVwg5-938uVArc&hl=tl&ei=4jI-Ssm8Ap7cMKDT9a0O&sa=X&oi=book_result&ct=result&resnum=1

2. Türker S.; Onur E.; Ózer Y. Nasal Route and Drug Delivery System. Pharmacy World and Science. Vol 26. June 2004. pp. 137-142. Springer

http://www.ingentaconnect.com/content/klu/phar/2004/00000026/00000003/05269011?crawler=true

Spoiler:

@krisna/to any of our classmates

Its been said in the study that Developing new pharmacologic methods are highly appreciated because new discoveries means improvement and I agreed with that. Is there any existing studies nowadays wherein new pharmacologic method has been developed?

Is there any existing studies nowadays wherein new pharmacologic method has been developed?

i saw one pharmaceutical company developing an influenza vaccine patch but was dated 2007, i researched about the availability of this patch and i learned thats its still under development. i think transdermal patch would be more popular compared to the powdered form because according to its developer 3m drug delivery sytem it would be a self administered vaccine.

another study from Frolov VG about transdermal patch vaccine reported that transdermal patch was not affected by long storage, and was not affected by refrigerated or room temperature conditions. they concluded that the product can tolerate unexpected environmental stresses.


http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/about-3M-Drug-Delivery/news/?PC_7_RJH9U5230O73F02RQG9R9E1OH0_assetId=1180605875315

http://www.pipelinereview.com/index.php/2007052612031/Influenza/Iomai-Announces-Interim-Results-From-Phase-1-Study-of-Its-Patch-Based-Vaccine-for-Seasonal-Influenza.html

Frolov VG et al.(2008 march)Transcutaneous delivery and thermostability of a dry trivalent inactivated influenza vaccine patch.
http://www.ncbi.nlm.nih.gov/pubmed/19453472?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Influenza viruses can affect anyone, but rates of infection are highest among children. Serious illnesses and death also occur in all age groups but rates are greatest in persons over the age of 65 years and those who have chronic health problems. Influenza is spread through coughing and sneezing, and is highly contagious, especially in childcare centers, schools, and nursing homes. Uncomplicated influenza generally comes on suddenly, and symptoms include muscle aches, fever, chills, headache, cough, and runny nose; it lasts for 3-7 days although cough can persist for about 2 weeks. The respiratory illnesses caused by influenza viruses are clinically difficult to distinguish from the illnesses caused by other respiratory infections. Young infants may have symptoms that mimic invasive bacterial infections with high fevers and fussiness, leading to hospitalization. Although most young children who are hospitalized with influenza virus infections are only in the hospital for a few days, some require treatment in an intensive care unit. The majority of children who are hospitalized for influenza infection are less than 5 years of age and a quarter of them are less than 6 months old. Influenza viruses can cause viral pneumonia, can make underlying medical conditions worse, and can lead to bacterial pneumonia, sinusitis and ear infections. Influenza virus infections have also been associated with inflammation of the heart and, brain swelling with liver failure.


Influenza vaccines have been used since 1945. Each year, the vaccines contain three virus strains that are expected to affect the United States in the upcoming winter. Until recently, all available influenza vaccines were trivalent inactivated (killed) influenza virus vaccines (TIV). Inactivated influenza virus vaccines cannot cause influenza. TIV came in whole-virus and split-virus forms prior to 2001; however, because of fewer side effects, including fever and reactions at the injection site, only split-virus TIVs are currently available in the U.S. In June of 2003, a live, attenuated, cold adapted, temperature sensitive, trivalent influenza virus vaccine (LAIV) was licensed in the United States. The temperature sensitive type A and B strains of influenza virus contained in LAIV replicate (multiply) in the nasal passages but not in the lower respiratory tract. Due to the change in the types of influenza viruses circulating each year, some of the virus components of the influenza vaccines must be changed as well.

There is growing interest in the development of stable powder vaccine formulations and delivery technologies to overcome refrigerated storage and distribution (ie, “cold chain”) requirements associated with liquid-based vaccine stability and delivery. Dry powder formulations are potentially superior to liquid formulations in that they do not support microbial growth and are more stable, eliminating the necessity of the cold chain, thereby facilitating mass vaccination particularly in the developing world. There is an urgent need not only to overcome cold chain requirements (for improved stability), but also to provide single-use, nonrefillable delivery technologies that require minimal training. Intranasal administration offers protection from influenza, since the virus uses the nasal route of entry to the host and intranasal (IN) vaccine elicits both a local and systemic immune response. This approach may ultimately provide a safe and effective alternative to the currently available influenza vaccines.

This vaccine provides distinct advantages in meeting the critical needs for influenza pandemic preparedness and epidemic control, including room temperature stability, broader protection, antigen sparing, ease of administration and induction of both mucosal and systemic immune responses.

The powder vaccine was found to be stable at ambient temperature for over eighteen months. A new vaccine, which can be distributed without refrigeration and is stable at room temperature for prolonged periods, could ease the threat of supply problems with pandemic influenza vaccines by allowing safe stockpiling of the treatment.

The vaccine appears to be an answer to the logistics and storage problems that are associated with such a therapy.

In coupling the vaccine with DelSite Biotechnology's GelVac nasal powder vaccine delivery system, the dry powder formulation provides several potential advantages including better stability, room temperature storage and no need for mercury or other preservatives. Nasal immunisation induces both systemic and mucosal immune responses.

Quote:

"Because GelVac vaccines contain no preservatives and are stable at room temperature for prolonged periods, they can be distributed without refrigeration through regular distribution channels and can easily be stockpiled until needed,"

"

Quote:

"In the case of a global flu pandemic, GelVac can be rapidly shipped to ensure efficient inoculation of our population."

REFERENCES:

1.S. P. Newman, G. R. Pitcairn, and R. N. Dalby. Drug delivery to the nasal cavity: in vitro and in vivo assessment. Crit. Rev. Ther. Drug Carrier Syst.21:21–66 (2004).

2.D. Chen, M. Burger, Q. Chu, R. Endres, C. Zuleger, H. Dean, and L. G. Payne. Epidermal powder immunization: cellular and molecular mechanisms for enhancing vaccine immunogenicity. Virus Res.103:147–153 (2004).

3.D. Chen, S. B. Periwal, K. Larrivee, C. Zuleger, C. A. Erickson, R. L. Endres, and L. G. Payne. Serum and mucosal immune responses to an inactivated influenza virus vaccine induced by epidermal powder immunization. J. Virol.75:7956–7965 (2001).

True enough, accessibility-wise, vaccines can be transported and distributed to certain areas, or in other countries, without having to maintain a certain temperature unlike the vaccines in liquid form.

According to the thesis that I have read, temperature has always been an issue for drug potency. As mentioned in the study of Amorij (2007), one rationale for development of stabilized vaccine formulation is the cold chain.


Inactivated influenza vaccines are temperature sensitive and must be stored at 2 to 8°C. Elevated temperatures can cause inactivation of the vaccine antigens, while temperatures below freezing result in formation of ice and solute concentration that may cause denaturation of the antigen.(Meulenaar, 2008)


The narrow temperature range makes the process of
distribution and storage complicated, fragile and costly. Although it was demonstrated that the influenza subunit vaccine could be stored for a couple of days outside the refrigerator at room temperature, vaccine distribution remains one of the greatest risk for vaccine quality, especially when the vaccine passes the central storage depots.(Tolboom, 2006)




References:

Amorij JP, Meulenaar J, Hinrichs WL, Stegmann T, Huckriede A, Coenen F, et al. Rational design of an
Influenza subunit vaccine powder with sugar glass technology: Preventing conformational changes of
haemagglutinin during freezing and freeze-drying. Vaccine 2007. http://dissertations.ub.rug.nl/FILES/faculties/science/2008/j.p.amorij/thesis.pdf

Be warned! Flu vaccine may pose a risk.

1. Guillain-Barré syndrome (GBS).
The chance of developing GBS is one person per 100,000 people. GBS is an illness that can cause muscle paralysis, pneumonia and death because of lung collapse due to weakness of muscles responsible for breathing. In the year 1976, swine flu vaccine was associated with getting GBS. Studies have done to evaluate if other types of flu vaccines may cause this side effect, only one of the vaccine was associated with GBS.

2. Allergic to eggs
Those who are allergic to eggs are cautioned to get a flu vaccine because the vaccine is manufactured using eggs.

But there is a recent study that flu vaccine can be safely be given to children who have an allergy to eggs because it contains egg protein. - According to Dr. Audrey Park, an allergist from the Children’s Hospital of Philadelphia who presented the research to the American Academy of Allergy, Asthma & Immunology.

http://www.whale.to/vaccines/gbs.htm
http://www.cdc.gov/flu/about/qa/flushot.htm
http://www.vaccinetruth.org/how_vaccine_is_made.htm
http://www.webmd.com/allergies/news/20080319/flu-vaccine-safe-for-egg-allergic-kids?src=rss_investeap

Influenza vaccine have been widely used today especially with the influenza A pandemic. In the study i have read, it said that certain strains of influenza may be suggested that a lower strain of vaccine be given to certain people to lower the level being administered, i a way of intradermal injection. And in the study three vaccines were tested to be used which are the following:

i) a whole inactivated influenza virus,
(ii) a trivalent split-virion human vaccine, and
(iii) a plasmid DNA encoding the influenza virus hemagglutinin

Reference:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1865614&tool=pmcentrez