Tim Wright, Editor05.07.18
SGS is a life sciences contract research organization (CRO) providing clinical research solutions as well as bioanalytical, biologics characterization, biosafety, and quality control testing. From a European base in Belgium, SGS offers a wide range of clinical services across Europe and the Americas, including first-in-human (FIH) studies, human challenge testing, biosimilars and complex PK/PD studies with a focus on infectious diseases, vaccines and respiratory therapeutics. In 2017, SGS Clinical Research announced the development of a novel, H3N2 influenza strain to be used as a challenge agent in human challenge trials to develop next-generation vaccines against the virus.
Contract Pharma spoke with SGS’s project director of its human challenge unit, Adrian Wildfire, to talk vaccine development and SGS’s unique position in this niche market space.
Contract Pharma: What are the current challenges in flu vaccine development?
Adrian Wildfire: The primary challenge in flu vaccine development, as with any vaccine, is demonstrating early proof of safety and efficacy that translate into the field. It is preferable that any new vaccine is capable of generating a long-term, protective response leading to immunity to infection without inducing symptoms similar to the disease itself. The lack of correlates of immunity for many disease causing agents has also delayed the development of effective interventions where a threshold value or indicative titer is desirable to estimate a protective index.
Specific to influenza, the development and testing regimes need to be accelerated to meet the needs of a seasonal vaccine. Thus, ‘normal’ or regularized systems of manufacture and quality assessment need to be adapted to ensure the availability of a strain-specific vaccine each year. Such seasonal vaccines are especially important to protect the more vulnerable populations such as the very young, the elderly and those with concomitant disease from infection. However, in a pandemic season, where a particularly virulent and pathogenic strain predominates, the general population needs to be protected both rapidly and with a high degree of ‘vaccine effectiveness’ to reduce the impact on individuals and society and to reduce or slow the global transmission of a novel influenza virus. Failure to provide such timely intervention may be seen in the Spanish Flu epidemic of 1918-1919 which killed more people than both the World Wars combined.
Traditionally, vaccines are tested at Early Phase (clinical testing) within a community setting using large numbers—up to many hundreds—of people who are inoculated with a developmental vaccine against naturally circulating strains of virus. The trials rely upon a sufficient number of people encountering the virus to be statistically relevant to allow the vaccine’s protective index to be calculated. Obviously, if the incidence of infection is low, this may not be possible and may result in a seasonal vaccine having a low vaccine effectiveness with many viruses being able to ‘escape’ the induced immunity and infect others. There is also the potential that other, novel circulating viruses can develop during the season or be imported into naïve populations causing ‘vaccine escape’ and, again, leading to an increase in infection rates.
CP: What are human challenge trials?
AW: A human challenge trial or study is designed to emulate the normal, wild type infections seen in communities, but in a more controlled environment. Challenge trials are performed in healthy volunteers, typically in groups or cohorts of 10-25 subjects, challenged or inoculated with a specific dose of a manufactured virus. This virus is chosen and manufactured to represent circulating strains found globally and commonly seen in outbreaks in many regions.
Participating subjects are healthy volunteers who are screened for antibodies to influenza to check their immunity status regarding the challenge agent. The subjects should not have encountered the virus selected as the challenge agent before, as they must be susceptible to infection. Subjects may be administered with a developmental vaccine or other prophylactic such as an antibody before being challenged with the target virus via a spray of virus in each nostril with an intranasal atomizer. During the infective period, subjects are held in a quarantine unit to avoid inward or outward transmission of infective agents.
Throughout the challenge trial, the symptoms and health of the subject and virus are monitored closely. The peak of influenza symptoms are normally reached in 72 hours post-infection, and by day 8, participants have fully recovered as measured by shed, or live virus, and symptomology and may be discharged into the community.
The design of challenge trials is slightly different from that of a traditional clinical trial in that the deliberate inoculation of a subject, subject isolation, the schedule of assessments and nature of the samples acquired are all well characterized within the context of a known infection start date. Field trials rarely, if ever, have precisely known start dates for infection and disease, making drug and vaccine analyses estimates of effect on disease initiation and/or progression difficult.
As previously stated, it is important that the challenge agent being used should be as close as possible to the currently circulating strains so that the naturally occurring disease is mimicked. The challenge agent should also be able to induce disease in healthy adults, have a known route of transmission, and demonstrate a well-defined disease progression in terms of the severity of symptoms and the signs and timing of their emergence to give the maximal correlation of interventions to outcomes.
CP: What are the advantages of controlled human infection models compared to other trials?
AW: Controlled human infection or human challenge trials are principally used for dose finding and proof of concept, but more commercial aspects of the vaccine may be assessed too. Compared to a traditional phase II field study, the cohort size for a challenge study is much smaller: typically, 60–100 subjects, compared to even a small field study which may require 200 to 300 subjects. In the field, the attack rate or rate of infection is typically low, around 5 to 10 percent, and is dependent on the prevalence of the infective agent in the population studied. Also there is no way of knowing when a subject may have contracted the infection. Lower numbers in a challenge trial are enabled by both a high attack rate and a good profile for virus shedding and symptoms compared to field studies i.e., the delta of change is larger and more easily measured so requires a smaller burden of proof to be significant.
The lower number of participants required for a challenge trial, and its controlled nature offer a significant cost saving. A challenge study may typically cost $2–3 million, whereas a field trial is likely to cost $5-6 million and requires up to ten times the number of subjects, and potentially two influenza seasons to complete.
Vaccine and drug trials require sampling events to be scheduled at critical periods, so that symptomology can be carefully monitored throughout. Human challenge trials allow these interventions to be scheduled precisely, allowing an assessment as to whether the timing of doses is critical to the therapy’s effectiveness to be made.
Correctly designed and executed, a human challenge trial can act as a cost-effective bridge to wider field trials, allowing alterations to the therapeutic dosage or dosing schedule to be made before expensive large-scale trials are embarked upon.
CP: What does the H3N2 virus allow to be done that was previously not possible?
AW: Selecting the optimal strain is an important part of achieving a successful trial for influenza therapeutics and vaccines and the prevention of future pandemic diseases. The new challenge strain developed by SGS (A/Belgium/4217/2015 [H3N2]), has been successfully tested in both a first-in-human and a commercial challenge trial. The virus has a high attack rate and a good shedding profile, allowing for accurate measures of efficacy against viral fitness and interruption of transmission.
The strain has also been proven to be a strong predictor of the outcomes of interventions on disease as it has clear and consistent symptomology, consistent with a mild, wild-type influenza infection. Such a retention of wild type characteristics is an important consideration when developing any challenge agent.
CP: How does the work with Bavarian Nordic follow on from the H3N2 virus?
AW: We recently announced a collaboration with Bavarian Nordic to develop a new, cGMP compliant respiratory syncytial virus, or RSV challenge strain.
RSV is highly infectious and is the most common cause of lower respiratory tract infections in pediatric populations, as well as being a serious health concern in the elderly and in adults with cardiopulmonary disease. According to World Health Organization estimates, RSV infects more than 64 million people globally each year and causes a similar number of deaths to those caused by influenza.
Unlike influenza, there is no vaccine to prevent RSV, which exhibits only two subtypes, typically present either simultaneously or alternately during yearly epidemics.
This partnership between SGS and Bavarian Nordic combines expertise from both companies with a view to bringing a life changing therapy to the market, with SGS offering its experience in both virus development and conducting human challenge trials safely and to exacting, international standards.
CP: What else/other disease targets could this type of work lead to?
AW: Regulatory authorities have, to date, been understandably cautious about promoting the concept of a human challenge trial, as it necessarily uses live infectious agents and makes people ill. However, where a trial is run in an approved unit with effective containment; and where the challenge agent is an effective surrogate for the wild type infection, then such studies are likely to gain approval.
At the moment, viral challenge trials are largely limited to upper respiratory tract infections, such as influenza, RSV, and the common cold. However, it is possible that over time, and as regulatory authorities become more confident with the challenge model, we may see it used to combat more virulent viruses such as dengue fever and Zika. There is already extensive work going on with challenge trials using bacterial isolates such as Salmonella, Shigella, Vibrio cholera, Escherichia coli and Streptococcus pneumoniae, and even malarial parasites in many centers in Europe and the U.S. and new organisms are being safely adopted as challenge agents on a seemingly monthly basis. It may not be too far-fetched to think that in the future, we may see the use of replicatory deficient agents being used to model chronic infections such as HIV or hepatitis.
CP: What is the future for vaccine development?
AW: The future for vaccine development is currently bright. As disease processes and immuno-logical interactions are better understood for each infective agent, a picture is emerging of the essential cellular and humoral components required for an effective protective or a sterilizing response. The use of gene-activation assays to study cell signaling, such as interleukin and receptor usage in cell-modulation, has highlighted the blunt nature of many previous approaches to promoting protective immunity. Despite a limited understanding of disease pathways, oral live polio and the ubiquitous BCG have been effective interventions for decades without us fully appreciating the subtleties of a live organism versus purified antigen challenge and their effects on disease and epidemiology.
The use of subunit vaccines may decrease as the realization of reduced protective windows, the necessity for conjugation and repeated boosting plus the homotypic effect of many such vaccines is seen as less desirable in the face of challenge with live, attenuated organisms or genetic vaccination. For example, small interfering RNA vaccines offer the potential to interrupt disease processes through gene-silencing of target, viral messenger RNA and also to stimulate interferon in host cells in the antiviral state; such RNA therapies may therefore directly ameliorate disease and interrupt viral replication without the need for inflammatory processes and concomitant symptoms. Delivery mechanisms remain the largest hurdle to adoption of siRNAs—such material having a short serum half-life.
Novel plasmid-DNA and RNA vaccines in carrier molecules such as lipid nanoparticles are being developed by many infectious disease companies and in clinical trials have been shown to be effective as a single ‘prime’ dose, directly inoculated into patient tissues without the need for boosters, combining the advantages of the safety of a sub-unit vaccine with the robust and prolonged effect of a live virus vaccine.
Alongside new preparations, new delivery devices and techniques are being developed. Electroporation offers a method of directly inserting RNA and DNA, coding for viral antigens, into host cells. This genetic material is then translated into antigens which are presented at the host cell surface, stimulating a profound immunological response without the need for the immune system to ever encounter live, infectious virus or suffer disease.
Such theoretical advances can be tested against target viruses in the human challenge model and the most promising candidates selected according to direct measures of efficacy. Many new approaches to vaccination are currently being considered by diverse groups in academia, biotechs and big pharma. It is an exciting time to be in research—both interventions and the outcomes can be assessed with direct relevance to performance in the community. This is seeing a revolution in pipeline development which will pay dividends in healthcare over the coming decade.
Contract Pharma spoke with SGS’s project director of its human challenge unit, Adrian Wildfire, to talk vaccine development and SGS’s unique position in this niche market space.
Contract Pharma: What are the current challenges in flu vaccine development?
Adrian Wildfire: The primary challenge in flu vaccine development, as with any vaccine, is demonstrating early proof of safety and efficacy that translate into the field. It is preferable that any new vaccine is capable of generating a long-term, protective response leading to immunity to infection without inducing symptoms similar to the disease itself. The lack of correlates of immunity for many disease causing agents has also delayed the development of effective interventions where a threshold value or indicative titer is desirable to estimate a protective index.
Specific to influenza, the development and testing regimes need to be accelerated to meet the needs of a seasonal vaccine. Thus, ‘normal’ or regularized systems of manufacture and quality assessment need to be adapted to ensure the availability of a strain-specific vaccine each year. Such seasonal vaccines are especially important to protect the more vulnerable populations such as the very young, the elderly and those with concomitant disease from infection. However, in a pandemic season, where a particularly virulent and pathogenic strain predominates, the general population needs to be protected both rapidly and with a high degree of ‘vaccine effectiveness’ to reduce the impact on individuals and society and to reduce or slow the global transmission of a novel influenza virus. Failure to provide such timely intervention may be seen in the Spanish Flu epidemic of 1918-1919 which killed more people than both the World Wars combined.
Traditionally, vaccines are tested at Early Phase (clinical testing) within a community setting using large numbers—up to many hundreds—of people who are inoculated with a developmental vaccine against naturally circulating strains of virus. The trials rely upon a sufficient number of people encountering the virus to be statistically relevant to allow the vaccine’s protective index to be calculated. Obviously, if the incidence of infection is low, this may not be possible and may result in a seasonal vaccine having a low vaccine effectiveness with many viruses being able to ‘escape’ the induced immunity and infect others. There is also the potential that other, novel circulating viruses can develop during the season or be imported into naïve populations causing ‘vaccine escape’ and, again, leading to an increase in infection rates.
CP: What are human challenge trials?
AW: A human challenge trial or study is designed to emulate the normal, wild type infections seen in communities, but in a more controlled environment. Challenge trials are performed in healthy volunteers, typically in groups or cohorts of 10-25 subjects, challenged or inoculated with a specific dose of a manufactured virus. This virus is chosen and manufactured to represent circulating strains found globally and commonly seen in outbreaks in many regions.
Participating subjects are healthy volunteers who are screened for antibodies to influenza to check their immunity status regarding the challenge agent. The subjects should not have encountered the virus selected as the challenge agent before, as they must be susceptible to infection. Subjects may be administered with a developmental vaccine or other prophylactic such as an antibody before being challenged with the target virus via a spray of virus in each nostril with an intranasal atomizer. During the infective period, subjects are held in a quarantine unit to avoid inward or outward transmission of infective agents.
Throughout the challenge trial, the symptoms and health of the subject and virus are monitored closely. The peak of influenza symptoms are normally reached in 72 hours post-infection, and by day 8, participants have fully recovered as measured by shed, or live virus, and symptomology and may be discharged into the community.
The design of challenge trials is slightly different from that of a traditional clinical trial in that the deliberate inoculation of a subject, subject isolation, the schedule of assessments and nature of the samples acquired are all well characterized within the context of a known infection start date. Field trials rarely, if ever, have precisely known start dates for infection and disease, making drug and vaccine analyses estimates of effect on disease initiation and/or progression difficult.
As previously stated, it is important that the challenge agent being used should be as close as possible to the currently circulating strains so that the naturally occurring disease is mimicked. The challenge agent should also be able to induce disease in healthy adults, have a known route of transmission, and demonstrate a well-defined disease progression in terms of the severity of symptoms and the signs and timing of their emergence to give the maximal correlation of interventions to outcomes.
CP: What are the advantages of controlled human infection models compared to other trials?
AW: Controlled human infection or human challenge trials are principally used for dose finding and proof of concept, but more commercial aspects of the vaccine may be assessed too. Compared to a traditional phase II field study, the cohort size for a challenge study is much smaller: typically, 60–100 subjects, compared to even a small field study which may require 200 to 300 subjects. In the field, the attack rate or rate of infection is typically low, around 5 to 10 percent, and is dependent on the prevalence of the infective agent in the population studied. Also there is no way of knowing when a subject may have contracted the infection. Lower numbers in a challenge trial are enabled by both a high attack rate and a good profile for virus shedding and symptoms compared to field studies i.e., the delta of change is larger and more easily measured so requires a smaller burden of proof to be significant.
The lower number of participants required for a challenge trial, and its controlled nature offer a significant cost saving. A challenge study may typically cost $2–3 million, whereas a field trial is likely to cost $5-6 million and requires up to ten times the number of subjects, and potentially two influenza seasons to complete.
Vaccine and drug trials require sampling events to be scheduled at critical periods, so that symptomology can be carefully monitored throughout. Human challenge trials allow these interventions to be scheduled precisely, allowing an assessment as to whether the timing of doses is critical to the therapy’s effectiveness to be made.
Correctly designed and executed, a human challenge trial can act as a cost-effective bridge to wider field trials, allowing alterations to the therapeutic dosage or dosing schedule to be made before expensive large-scale trials are embarked upon.
CP: What does the H3N2 virus allow to be done that was previously not possible?
AW: Selecting the optimal strain is an important part of achieving a successful trial for influenza therapeutics and vaccines and the prevention of future pandemic diseases. The new challenge strain developed by SGS (A/Belgium/4217/2015 [H3N2]), has been successfully tested in both a first-in-human and a commercial challenge trial. The virus has a high attack rate and a good shedding profile, allowing for accurate measures of efficacy against viral fitness and interruption of transmission.
The strain has also been proven to be a strong predictor of the outcomes of interventions on disease as it has clear and consistent symptomology, consistent with a mild, wild-type influenza infection. Such a retention of wild type characteristics is an important consideration when developing any challenge agent.
CP: How does the work with Bavarian Nordic follow on from the H3N2 virus?
AW: We recently announced a collaboration with Bavarian Nordic to develop a new, cGMP compliant respiratory syncytial virus, or RSV challenge strain.
RSV is highly infectious and is the most common cause of lower respiratory tract infections in pediatric populations, as well as being a serious health concern in the elderly and in adults with cardiopulmonary disease. According to World Health Organization estimates, RSV infects more than 64 million people globally each year and causes a similar number of deaths to those caused by influenza.
Unlike influenza, there is no vaccine to prevent RSV, which exhibits only two subtypes, typically present either simultaneously or alternately during yearly epidemics.
This partnership between SGS and Bavarian Nordic combines expertise from both companies with a view to bringing a life changing therapy to the market, with SGS offering its experience in both virus development and conducting human challenge trials safely and to exacting, international standards.
CP: What else/other disease targets could this type of work lead to?
AW: Regulatory authorities have, to date, been understandably cautious about promoting the concept of a human challenge trial, as it necessarily uses live infectious agents and makes people ill. However, where a trial is run in an approved unit with effective containment; and where the challenge agent is an effective surrogate for the wild type infection, then such studies are likely to gain approval.
At the moment, viral challenge trials are largely limited to upper respiratory tract infections, such as influenza, RSV, and the common cold. However, it is possible that over time, and as regulatory authorities become more confident with the challenge model, we may see it used to combat more virulent viruses such as dengue fever and Zika. There is already extensive work going on with challenge trials using bacterial isolates such as Salmonella, Shigella, Vibrio cholera, Escherichia coli and Streptococcus pneumoniae, and even malarial parasites in many centers in Europe and the U.S. and new organisms are being safely adopted as challenge agents on a seemingly monthly basis. It may not be too far-fetched to think that in the future, we may see the use of replicatory deficient agents being used to model chronic infections such as HIV or hepatitis.
CP: What is the future for vaccine development?
AW: The future for vaccine development is currently bright. As disease processes and immuno-logical interactions are better understood for each infective agent, a picture is emerging of the essential cellular and humoral components required for an effective protective or a sterilizing response. The use of gene-activation assays to study cell signaling, such as interleukin and receptor usage in cell-modulation, has highlighted the blunt nature of many previous approaches to promoting protective immunity. Despite a limited understanding of disease pathways, oral live polio and the ubiquitous BCG have been effective interventions for decades without us fully appreciating the subtleties of a live organism versus purified antigen challenge and their effects on disease and epidemiology.
The use of subunit vaccines may decrease as the realization of reduced protective windows, the necessity for conjugation and repeated boosting plus the homotypic effect of many such vaccines is seen as less desirable in the face of challenge with live, attenuated organisms or genetic vaccination. For example, small interfering RNA vaccines offer the potential to interrupt disease processes through gene-silencing of target, viral messenger RNA and also to stimulate interferon in host cells in the antiviral state; such RNA therapies may therefore directly ameliorate disease and interrupt viral replication without the need for inflammatory processes and concomitant symptoms. Delivery mechanisms remain the largest hurdle to adoption of siRNAs—such material having a short serum half-life.
Novel plasmid-DNA and RNA vaccines in carrier molecules such as lipid nanoparticles are being developed by many infectious disease companies and in clinical trials have been shown to be effective as a single ‘prime’ dose, directly inoculated into patient tissues without the need for boosters, combining the advantages of the safety of a sub-unit vaccine with the robust and prolonged effect of a live virus vaccine.
Alongside new preparations, new delivery devices and techniques are being developed. Electroporation offers a method of directly inserting RNA and DNA, coding for viral antigens, into host cells. This genetic material is then translated into antigens which are presented at the host cell surface, stimulating a profound immunological response without the need for the immune system to ever encounter live, infectious virus or suffer disease.
Such theoretical advances can be tested against target viruses in the human challenge model and the most promising candidates selected according to direct measures of efficacy. Many new approaches to vaccination are currently being considered by diverse groups in academia, biotechs and big pharma. It is an exciting time to be in research—both interventions and the outcomes can be assessed with direct relevance to performance in the community. This is seeing a revolution in pipeline development which will pay dividends in healthcare over the coming decade.
