Global Vaccines

Global Vaccines, Inc is a mission-driven non-profit company applying state-of-the-art science and innovative business strategies to design and develop affordable vaccines for people in poor countries.

Origins

In 2006, Robert E. Johnston, Ph.D., opened the doors of Global Vaccines, Inc (GVI), a not-for-profit company, spinning out from the University of North Carolina at Chapel Hill, in order to develop new vaccines free from the limitations of high profit-margin requirements. The company develops platform vaccine technologies that can be applied to a broad spectrum of disease targets selected on the basis of global public health needs rather than market potential. It is located in the Research Triangle Park in North Carolina.

Challenges

Polio, malaria, rotavirus, HIV – these diseases hit the poorest people on earth the hardest, with millions of new infections each year. On top of the sheer human suffering involved, the economic impact of this disease burden on affected countries is severe.

But poor countries simply can't afford the high cost of creating new vaccines to prevent these diseases, and companies from developed countries won't invest in vaccines that have little market value.

The Global Vaccines Solution

Global Vaccines, Inc. develops and acquires new vaccine technologies that can be used to fight diseases of both the developed and developing worlds.

They sublicense these new technologies to commercial companies for use in more profitable markets, giving them the financial ability to continue developing these technologies to help the globe's poorest.

It's a win-win formula – commercial companies acquire more mature technologies for a less risky investment, and the developing world gets the vaccines it needs.

In several preclinical trials, Global Vaccines' novel technologies have already shown remarkable promise across a range of disease targets.[1] [2]

Technology 1 – Novel adjuvant

About adjuvant technology

A vaccine adjuvant is basically a booster for vaccines. It is a component that can be added to a vaccine to increase the level of immunity that the vaccine can induce. This technology can quantitatively and qualitatively improve vaccine performance, reduce the per dose production cost of some existing vaccines by up to 50 fold, and make production of new vaccines possible. With a safe and powerful adjuvant, certain expensive vaccine designs can be made more effective and therefore, more feasible and affordable.

GVI is creating an entirely new class of adjuvant

The GVI adjuvant takes a totally different approach from that of existing adjuvant types. GVI modified a small RNA virus so that it can infect cells in lymph nodes (the hubs of the immune system) and induce a strong and broadly-based innate response. The virus adjuvant is safe, as it is engineered so that it cannot reproduce new viruses and cannot spread beyond the initially infected cells. When simply mixed with killed virus vaccines or soluble proteins, there is a very strong quantitative enhancement of the antibody response (10–50 fold) relative to the killed virus or soluble protein alone. Moreover, systemic cellular immunity is induced, as well as mucosal cellular and antibody responses. [3] [4] [5] Virtually no cellular or mucosal responses are detected in animals receiving the killed vaccine or soluble protein alone.

Other advantages of the GVI adjuvant include the ability to augment response to multiple immunogens in a single inoculation without special formulation. This suggests the possibility of 1) using multiple subunit proteins from a complex pathogen in the same vaccine, and 2) using multiple strains of the same pathogen in a vaccine to broaden coverage for organisms that display a high degree of variability such as influenza and HIV/AIDS.

GVI is making progress toward applying the GVI adjuvant to vaccines for a range of diseases. The NIH is currently funding their investigation into the role of the innate immune system on the activity of the GVI adjuvant.

Technology 2 – New live attenuated virus vaccines

About this type of vaccine

Live attenuated vaccines historically have been the most effective intervention in the fight to prevent infectious diseases. Such vaccines have eliminated smallpox from the entire globe and polio from the Western hemisphere. The incidence of measles, mumps, rubella, and chickenpox have been greatly reduced in those regions with high percentages of vaccinated individuals.

In addition to their efficacy, live attenuated vaccines are relatively inexpensive to produce. However, there is an extremely low but finite risk with all of these vaccines that they can revert to being virulent again. In the case of the Sabin polio vaccine, some circulating poliovirus strains that have caused local epidemics have been traced to vaccine revertants. This means that live attenuated vaccines are unlikely to be used for certain high profile lethal diseases.

GVI's live attenuated chimeric virus vaccine

Global Vaccines has licensed a technology that allows directed molecular construction of live attenuated virus vaccines using a genetic component from one virus and the antigenic elements from the virus targeted by the vaccine. These chimeric vaccines are predicted to be safe, very unlikely to revert, and highly efficacious.[6]

HIV Chimeric Virus Vaccine Program

The search for an HIV vaccine has been ongoing for decades. In all that time, only one approach has appeared to be strongly protective in the monkey model for AIDS, which is known as simian immunodeficiency virus (SIV). Deletion of a portion of the SIV genome resulted in a virus that could grow in cell culture but failed to cause AIDS in monkeys. When animals inoculated with this attenuated virus were challenged again with virulent SIV, they were protected from the otherwise lethal infection.[7] The mechanism by which protection is mediated is likely to be through a T-cell response elicited by the first inoculation. Although this suggested that a live attenuated vaccine might protect against HIV, the approach was considered far too risky to try in humans.

Disease Targets

Currently, Global Vaccines focusing on developing vaccine technologies for use against a range of diseases. Follow the links below to learn more about current disease targets and the technologies Global Vaccines has been developing to address these disease pathogens:

Poliovirus

Polio vaccine program

Poliovirus is an enterovirus which is transmitted by the fecal-oral route. The virus is ingested, transits the stomach, and replicates in the lining of the gut where it causes a short-term diarrhea. There are two types of poliovirus vaccines in current use. One is the killed Salk vaccine, which consists of chemically inactivated wild poliovirus. The Salk vaccine is administered intramuscularly, and being a killed vaccine, predominantly induces systemic antibodies. However, the Salk vaccine does not induce strong mucosal immunity, so poliovirus can replicate freely in the intestines of even vaccinated individuals, and the infection can then be spread to unvaccinated contacts.

The second vaccine is the Sabin vaccine, which is a live attenuated vaccine. The Sabin vaccine is given orally, replicates in the intestines of vaccines, induces both mucosal and systemic immunity, and protects against infection of the intestine by ingested virulent poliovirus. The Sabin vaccine also has drawbacks; notably, it can revert to a virulent form, and there are documented cases of circulating revertant Sabin poliovirus causing outbreaks of disease in areas from which the natural virus had been previously eradicated.[8][9]

Switching to the Salk vaccine may help solve this problem, but carries at least three liabilities. First, it is expensive to manufacture. Second, manufacture can only be done under high containment for fear of release of the virulent virus prior to chemical inactivation. And third, lack of protection in the gut would mean failure to interdict circulation of natural poliovirus. The GVI adjuvant has the potential to greatly improve vaccination with the Salk vaccine so that less of this expensive vaccine would be required and so that it would be capable of inducing mucosal immunity for protection of the gut. Because the Salk vaccine plus adjuvant would be delivered intramuscularly, immunization would not be prevented by an activated environment in the gut.

Malaria

Malaria Vaccine Program

Malaria is one of the world's most prevalent serious infectious diseases, with approximately 250 million cases and 1 million deaths per year.[10] Mortality is primarily in children under the age of five and in pregnant women. Every 45 seconds, an African child dies of malaria. The disease is transmitted from person to person by infected mosquitoes, so past eradication efforts involved massive insecticide campaigns.

The malaria disease-causing organism is Plasmodium falciparum, and to a lesser extent, P. vivax. Both parasites undergo multiple transformations during their life cycle in mosquitoes and in various cell types and organ systems in the human host. Several malaria proteins have been used individually as vaccines with sporadic results. A current Phase III clinical malaria vaccine trial in Africa conducted by a large commercial vaccine company, uses a proprietary adjuvant. The best results so far reduced clinical episodes by 53% in vaccinated children, but protection only lasted for 8 months.

The GVI adjuvant has the potential to significantly improve malaria vaccines. First, physical association of the adjuvant and antigen is not required, making it possible to rapidly evaluate the effectiveness of immunogens individually and in combination. Second, unlike other known adjuvants, the GVI adjuvant enhances and qualitatively improves the humoral antibody response and produces balanceed antibody and cellular immunity.

Collaborative experiments with the Walter Reed Army Institute for Research (WRAIR) have been extremely encouraging. A malaria protein supplied by WRAIR was simply mixed with the GVI adjuvant and administered to mice. Compared with the protein alone, the immunogen plus adjuvant gave an immune response that was at least 50 times higher. This is all the more impressive considering that the dose of protein in the adjuvanted group was 60% less than in the group that received the protein alone. This experiment has been successfully repeated, and serum samples shipped to WRAIR showed anti-malarial activity in laboratory assays.

Dengue fever

Dengue Fever Vaccine Program

Dengue fever, also known as breakbone fever, is a viral disease characterized by severe headache, skin rash and debilitating muscle and joint pain. The WHO estimates ~30 million new infections every year, some of which progress to more severe forms of the disease, characterized by circulatory failure, shock, coma and death. The disease is caused by any of four dengue virus serotypes, and is transmitted to humans by the Aedes aegypti mosquito, which has regained global distribution in the tropical and subtropical regions of the globe.

The development of a dengue vaccine has unique challenges. The four dengue serotypes circulate globally, and infection with one dengue serotype confers lifelong protection against re-infection with the same serotype, but only short-term protection against the other 3 serotypes. Moreover, dengue is unique in that sequential infections with different serotypes increase the risk of developing severe and potentially lethal disease. There is limited understanding of how the virus interacts with the immune system and how certain types of pre-existing immunity can exacerbate disease. Therefore, a safe and effective dengue vaccine must be tetravalent, and induce strong and long-lived protection against all 4 serotypes simultaneously in order to avoid the risk of sensitizing the vaccine recipient to severe disease.

There are a number of dengue vaccine candidates in different stages of development. The more advanced consist of tetravalent mixtures of live attenuated virus representing each serotype. One disadvantage of all live attenuated viruses candidates in clinical trials is that a single inoculation is not sufficient to induce protection to all 4 serotypes, probably due to viral interference among the live components of the vaccine. In addition, booster doses are not effective when administered less than 6 months apart. Therefore, live attenuated viruses require three immunizations over an extended dosing schedule of 12 months to elicit balanced neutralizing antibody responses to all 4 serotypes.

Influenza

Influenza (seasonal, pandemic, and avian) vaccine program

The promising activity of the GVI adjuvant and many of its characteristics have been demonstrated in mice with an inactivated vaccine for seasonal influenza (H1N1). Collaborating with the University of California at Davis, GVI has also shown a strong adjuvant effect in monkeys using a commercially available Sanofi H1N1 vaccine, Fluzone™. Systemic antibodies were increased by a factor of 20 in the monkeys that received Fluzone™ plus GVI adjuvant compared to animals receiving Fluzone™ alone, and the responses were uniformly high among the individual animals in the adjuvant group. Moreover, protective levels of antibody were achieved with a single inoculation in 5 out of 6 animals compared to 1 out of 6 in the Fluzone™ only group.

In the late 1990s and early 2000s, outbreaks of disease from the highly pathogenic avian influenza A H5N1 virus occurred, with human fatality rates as high as 50% in some instances. While human-to-human transmission of H5N1 has been very rare and unsustained, H5N1 virus infections among poultry have become endemic in certain regions and still cause sporadic human infections from direct contact with infected poultry.

The federal government has stockpiled an avian flu (H5N1) vaccine candidate manufactured under cGMP by Sanofi. However, the ability of this vaccine alone to induce protective immune responses in humans is poor, and the corresponding need for an effective adjuvant is clear.

GVI tested the Sanofi H5N1 vaccine in mice with and without the GVI adjuvant, collaborating with scientists at St. Jude Children's Research Hospital. Without the GVI adjuvant, there is little or no detectable response when measuring hemagglutination inhibition (HI) antibodies. HI antibodies are thought to correlate with protection in humans. With the GVI adjuvant, Global Vaccines demonstrated very strong HI responses. Moreover, cellular immunity and mucosal immunity were detected, and the responses were potent across a broad range of distantly related H5N1 isolates. Protection against challenge with virulent H5N1 was virtually complete with reductions of 3 to 4 orders of magnitude in challenge virus replication in the lung.

HIV

HIV vaccine program

Human immunodeficiency virus (HIV) is the most challenging vaccine target of our lifetime. All traditional approaches have been unsuccessful so far, as have many innovative new approaches. Recently, a Phase III trial combining two approaches, which had failed in individual trials, gave some indication of success. This involved a first inoculation with a poxvirus vaccine that had been engineered to express HIV proteins, and a second inoculation with a purified HIV protein. If the results are analyzed in the most favorable light, protection against infection reached statistical significance in about 30% of the subjects, but the protection lasted only 3-6 months. Nevertheless, decades after discovery of HIV, and the investment of untold time, money and research careers, even this modest indication that a protective vaccine might be possible was a very welcome result.

The GVI adjuvant could contribute significantly to improvement of this vaccination strategy. The capacity of the adjuvant to enhance antibody induction would be supplemented by its ability to induce cellular and mucosal immunity. Given that most HIV transmission globally is by heterosexual contact, the mucosal immunity aspect of the adjuvant may be of critical importance.

Live attenuated vaccines historically have been the most effective intervention in the fight to prevent infectious diseases. In the case of HIV, GVI has licensed a technology that allows directed molecular construction of live attenuated virus vaccines using a genetic component from one virus and the antigenic elements from the virus targeted by the vaccine. These chimeric vaccines are predicted to be safe, very unlikely to revert, and highly efficacious.

The Global Vaccines Team

References

Primary technology publications from GVI

  1. ↑ Carroll, Timothy D.; S. R. Matzinger, Mario Barro, L. Fritts, M. B. McChesney, C. J. Miller and Robert E. Johnston (2011). "Alphavirus replicon-based adjuvants enhance the immunogenicity and effectiveness of Fluzone® in rhesus macaques". Vaccine 29 (5): 931–940. doi:10.1016/j.vaccine.2010.11.024. PMC 3026063. PMID 21111777. Cite uses deprecated parameter |coauthors= (help)
  2. ↑ LoBue, Anna D.; Joseph M. Thompson, L. Lindesmith, Robert E. Johnston and Ralph S. Baric (2009). "Alphavirus-adjuvanted norovirus-like particle vaccines: heterologous, humoral, and mucosal immune responses protect against murine norovirus challenge". J. Virol. 83 (7): 3212–3227. doi:10.1128/JVI.01650-08. PMC 2655567. PMID 19176631. Cite uses deprecated parameter |coauthors= (help)
  3. ↑ Tonkin, Daniel R.; Patricia Jorquera; Tracie Todd; Clayton W. Beard; Robert E. Johnston; Mario Barro (2010). "Alphavirus replicon-based enhancement of mucosal and systemic immunity is linked to the innate response generated by primary immunization". Vaccine 28 (18): 3238–3246. doi:10.1016/j.vaccine.2010.02.010. PMC 2855431. PMID 20184975.
  4. ↑ Thompson, Joseph M.; Alan C. Whitmore; Herman F. Staats; Robert E. Johnston (2008). "The contribution of type 1 interferon signaling to mucosal IgA responses induced by alphavirus replicon vaccines". Vaccine 26 (39): 4998–2003. doi:10.1016/j.vaccine.2008.07.011. PMID 18656518.
  5. ↑ Thompson, Joseph M.; Alan C. Whitmore; Herman F. Staats; Robert E. Johnston (2008). "Alphavirus replicon particles acting as adjuvants promote CD8+ T cell responses to co-delivered antigen". Vaccine 26 (33): 4267–4275. doi:10.1016/j.vaccine.2008.05.046. PMID 18582997.
  6. ↑ Jurgens, CK*; Young, KR*, Madden, VJ, Johnson, PR, Johnston RE (2012). "A Novel Self-Replicating Chimeric Lentivirus-Like Particle". J. Virol. 86 (1): 246–261. doi:10.1128/JVI.05191-11. PMC 3255904. PMID 22013035. Cite uses deprecated parameter |coauthors= (help)
  7. ↑ Daniel, MD; Kirchhoff F.; Czajak SC; Sehgal PK; Desrosiers RC (1992). "Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene". Science. 5090 258: 1938–9141. doi:10.1126/science.1470917. PMID 1470917.
  8. ↑ "Circulation of a type 2 vaccine-delivered polovirus--Egypt". MMWR Morbidity and Mortality Weekly Report. 3 50: 41–42, 51. 2001.
  9. ↑ "Acute flaccid paralysis associated with circulating vaccine-derived poliovirus". MMWR Morbidity and Mortality Weekly Report. 40 50: 874–875. 2001.
  10. ↑ WHO, 2009

External links

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