Vaccination as a preventive measure for HIV-related cancers
Sareh Bagherichimeh, BSc
Contact: sbagher4@uwo.ca
January 20, 2021
The 38 million people who are infected with the human immunodeficiency virus (HIV) worldwide are susceptible to HIV-related cancers. Though antiretroviral therapy (ART) is very effective at treating HIV infection, it has not been as effective in eradicating HIV-related cancers, which greatly impede the quality of life and life expectancy of HIV infected individuals. Dr. Chil-Yong Kang at Western University has developed the first whole-killed HIV vaccine that is showing promise after a successful phase 1 clinical trial. A preventative measure such as the HIV vaccine being developed by Dr. Kang has the potential to address the wide range of HIV-related cancers.
HIV infects a major group of immune cells, called T-cells, decreasing their number and weakening an infected individual’s immune response. The human immune system fights not only foreign disease-causing agents, pathogens, but is also continuously fighting to eliminate damaged cells that can grow uncontrollably and become cancerous. As such, cancer cells can grow rapidly in an individual with a weakened immune system.
The significant improvements in HIV treatment with the advent of ART, which restores the number of immune cells, was expected to eliminate this increased risk of cancer in HIV-infected individuals. However, though there has been a significant decrease in occurrence of AIDS-defining cancers, there hasn’t been a significant decrease in non-AIDS-defining HIV-related cancers. There were 7 million new HIV infections last year, and HIV infected individuals are living longer as the use of combination ART is being perfected. Most cancer rates increase with age, and so too does the rate of HIV-related cancers, making HIV-related cancers a growing public health concern.
As the immune cell recovery achieved through ART hasn’t been able to eradicate HIV-related cancers, the weakened immune system is evidently not the only contributing factor in these cancers, and the reasons for the increased susceptibility are not fully understood. As a result, we are unable to tackle the various HIV-related cancers collectively. A cure for HIV is the most promising solution to address HIV-related cancers; the HIV vaccine developed by Dr. Kang’s lab having recently completed a successful phase one clinical trial is a promising preventative measure to tackle HIV-related cancers.
How Vaccines work
Vaccines simply familiarize our immune system to a specific disease-causing agent, known as a pathogen. The immune system has a memory of all the pathogens it has fought in the past, which greatly enhances its ability to fight recurring pathogens.
Once a pathogen enters our body there are two major lines of defense: the first one is an innate immune response, which is non-specific and immediate. In the second line of defense, the adaptive immune system develops a specific molecule that would bind to the pathogen called an antibody; vaccines make use of the second line of defense.
Having a specific antibody for a pathogen greatly enhances the immune system’s ability to recognize and eliminate that pathogen. However, developing this antibody to mount a significant adaptive immune response takes 4-7 days. Time is crucial in combating pathogens as once the pathogen enters our body, it is a race between the spread of the proliferating pathogen and our immune system. The adaptive immune system has a memory of all the pathogens it has developed in the past, which saves time on antibody development when encountering familiar pathogens – it makes the difference between life and death from a virulent infection.
Vaccines work by introducing our immune system to a pathogen in a safe way to gain immune memory of that pathogen’s specific antibody. There are a number of ways to safely interact with a pathogen. The whole pathogen can be killed or inactivated by various chemical, physical, or genetic means, or the pathogen can be broken into its parts and exposure to a subunit from the surface of the pathogen can suffice to mount an effective immune response.
The recently developed COVID mRNA vaccines contain the genetic material, messenger RNA (mRNA) that codes for a protein nearly identical to the surface spike protein of the SARS-CoV-2 virus. Our body can manufacture the protein from the genetic instructions in the form of the mRNA, introducing our immune system to the protein. This leads to the development of the antibody specific to the SARS-CoV-2 surface spike protein. When a vaccinated individual is exposed to the SARS-CoV-2 virus, the specific antibody for this pathogen will enable quick identification and eradication of the virus.
HIV Vaccines
Kang’s lab developed a killed whole-HIV vaccine and performed the first ever killed whole-HIV vaccine clinical trial. Killed whole viruses have been used to create effective vaccines against numerous viral diseases, however due to safety concerns they have long been avoided for use with HIV. In a previous attempt back in 2005, inactivation of the virus led to loss of the envelope glycoproteins, which are the surface molecules crucial for the detection of the virus by the immune system. Thanks to developments in inactivation methods, Kang’s lab was able to generate a completely inactivated vaccine suitable for mass production while maintaining the native structure of the virus, including its envelope glycoproteins. They used both a chemical (AT-2) and a physical (γ-irradiation) means of inactivation and, to further ensure safety, deleted one of the HIV genes that increases virus infectivity, the negative factor gene (nef).
The safety of the vaccine was confirmed outside of living organisms (in vitro) when they infected human T-cells with the vaccine and were unable to detect any residual infectious particles. They also tested the effectiveness of the vaccine in a living organism (in vivo) to mount an immune response by injecting it into mice and were able to confirm the vaccine induced the production of an antibody for a HIV envelope glycoprotein.
After overcoming the challenge of developing a killed whole-HIV vaccine, including production of the completely inactivated vaccine on a large scale, Kang’s lab was ready to evaluate the safety of this vaccine on humans. Testing a vaccine on humans begins with a phase 1 human clinical trial – the first of three clinical trials needed for vaccine approval. A randomized placebo-controlled clinical trial of Dr. Kang’s whole killed-HIV vaccine was carried out on 33 HIV-infected but otherwise healthy volunteers. Though the HIV vaccines is aimed to be a preventative measure against HIV, the phase 1 clinical study was carried out on HIV positive volunteers on ART to minimize risk of HIV infection.
The volunteers in the phase one clinical trial were randomly assigned to groups, in the first group, 12 volunteers were given the vaccine and 4 were given a placebo, a substance with no therapeutic value used as a control to compare against the effect of the therapeutic agent. In the second group, 13 participants were given a combination of the vaccine with an adjuvant while 4 were given a placebo with the adjuvant. An adjuvant is a common component of many vaccines as it helps the vaccine work better by irritating the immune system to evoke a stronger immune response.
The main objective of a phase one clinical trial is to examine how well the vaccine is tolerated within a small group of healthy individuals by monitoring adverse events in participants after vaccination. Adverse events can be physical events (e.g., a rash), a psychological event (e.g., depression), or a laboratory event (e.g., elevated blood sugar). No severe adverse events or adverse events leading to study termination were reported in any participant and the majority of subjects had no immediate whole-body or local reaction to the vaccine. With these results, Kang et al. were able to conclude that intramuscular administration of their killed whole-HIV vaccine is tolerable for human use.
The research group was also able to complete a preliminary analysis of the effectiveness of the vaccine to evoke an immune response. They compared the level of antibodies against a number of surface HIV proteins before and after the administration of the vaccine. Some increase was seen in individuals injected with the vaccine alone, but a significant increase was seen in individuals injected with the vaccine and adjuvant combination. Having confirmed the safety of this killed whole-HIV vaccine in humans, Dr. Kang plans on carrying out the phase 2 clinical trial on HIV negative but high-risk volunteers in order to examine the level of HIV-specific antibody production provoked by the vaccine; around 600 volunteers are needed in order to observe a meaningful difference.
There are currently a handful of HIV vaccines in development, but Dr. Kang’s is the first killed whole-HIV vaccine. In the past the biggest hurdle has been to develop a vaccine capable of inducing a specific and strong enough immune response to gain immune protection. Killed whole-vaccines are known for being able to mount a strong immune response. Therefore, there is a lot of excitement surrounding the killed whole-vaccine. After a successful phase 2 clinical trial, they’ll be able to examine the efficacy of the immune protection developed by the administration of the vaccine in the phase 3 clinical trial. The hope is for HIV to be one of many diseases we have successfully eradicated through vaccination.
How are vaccines approved for human use in Canada?
In Canada, Health Canada regulates vaccines. Vaccines are categorized as a biologic drug according to the Food and Drugs Act. They are distinguished from chemical drugs because they come from living organisms and require greater regulatory oversight. Health Canada’s Biologic and Radiopharmaceutical Drugs Directorate (BRDD) is the Canadian regulatory authority responsible for approving biological drugs. Before and after approval, the BRDD also has regulatory processes to ensure the highest quality of vaccine manufacturing, including inspecting the facilities to ensure good manufacturing practices and authorizing the release of every new lot of vaccines as they are produced.
Pre-clinical Trial
This is the research stage where scientists study the virus, its structure, and how it causes disease. Once a vaccine candidate has been identified, scientists conduct laboratory experiments to study vaccine candidates extensively. Once they have exhausted all they can learn about the efficacy and safety of the vaccine from studying it in vitro (outside of living organisms) and in vivo (in animal models), they are ready to begin studying the vaccine in humans.
Researchers or companies then compile all their data from these pre-clinical tests in an application to Health Canada for clinical trials. Health Canada carefully vets all data and determines whether Good Laboratory Practices were used to obtain that data. They also assess the vaccine’s quality and safety, including its manufacturing methods. By weighing the vaccine’s potential and its safety risks, they determine if it’s reasonably safe for human testing.
Phase 1
The vaccine candidate then moves into its first clinical trial stage. In phase one, the vaccine is tested on a small number of healthy volunteers (less than 100) and the focus is to determine how well the vaccine is tolerated by humans. Adverse events are closely monitored. Some preliminary evaluation of the vaccine’s efficacy can also be carried out in this stage.
Phase 2
If no safety concerns were observed in the phase 1 clinical trial, the vaccine candidates move to phase 2 in which they will be tested on a larger group (hundreds) of volunteers who have wider ranges of health statuses and demographics. This enables the researchers to perform a standardized evaluation of the vaccine’s ability to provoke an immune response.
Phase 3
If promising data on the efficacy of the vaccine and the absence of safety issues in the wider demographic range were observed, the vaccine candidate moves to phase 3. Here the vaccine candidate is tested in a randomized controlled study on a much larger scale (thousands of volunteers) who have an even larger range of demographics. Using a large group of volunteers enables the identification of less common side effects and, most importantly, enables the first-hand examination of the efficacy of the vaccine by comparing how many people in the vaccinated group versus the control group contracted the infection after certain amount of time. This determines if vaccination was able to reduce the incidence of infection.
It is only after the phase 3 clinical trial that the researchers can submit an application that gets thoroughly reviewed by Health Canada for approval. After approval, vaccines are continuously monitored, from the physicians and hospitals where they are administered to the provincial level where data is collected and sent to the Public Health Agency of Canada that monitors them on a federal level. Vaccines are further monitored on an international level by the World Health Organization, which receives reports on vaccines from 75 countries.
To learn more about…
Whole-killed HIV vaccine
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594480/
First clinical trial of the whole-killed HIV vaccine
https://doi.org/10.1186/s12977-016-0317-2
COVID-19 vaccine is being developed
How vaccines work
https://healthsci.mcmaster.ca/learningtechlab/news/2015/05/28/what-are-vaccines-and-how-do-they-work
History of vaccination
https://www.sciencemuseum.org.uk/objects-and-stories/medicine/smallpox-and-story-vaccination
Health Canada: Vaccination: are we there yet?
In French: https://www.youtube.com/user/CANenSante
Dr. Chil-Young Kang
References
Choi, E., Michalski, C.J., Choo, S.H. et al. (2016). First Phase I human clinical trial of a killed whole-HIV-1 vaccine: demonstration of its safety and enhancement of anti-HIV antibody responses. Retrovirology 13, 82 https://doi.org/10.1186/s12977-016-0317-2
Government of Canada. (2020) Regulating Vaccines for human use in Canada. https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/activities/fact-sheets/regulation-vaccines-human-canada.html
Foster, J. L., & Garcia, J. V. (2008). HIV-1 Nef: at the crossroads. Retrovirology, 5, 84. https://doi.org/10.1186/1742-4690-5-84
Kang, C. Y., & Gao, Y. (2017). Killed whole-HIV vaccine; employing a well established strategy for antiviral vaccines. AIDS research and therapy, 14(1), 47. https://doi.org/10.1186/s12981-017-0176-5
National Institute of Allergy and infectious Disease.(2019, July) Vaccine Types.OMB#: 0925-0668 https://www.niaid.nih.gov/research/vaccine-types
Riedel S. (2005). Edward Jenner and the history of smallpox and vaccination. Proceedings (Baylor University. Medical Center), 18(1), 21–25. https://doi.org/10.1080/08998280.2005.11928028
UNAIDS. (2020). Global HIV & AIDS statistics – 2020 fact sheet. https://www.unaids.org/en/resources/fact-sheet
US Department of Health and Human Services. (2020) Vaccine Types. Vaccines.gov https://www.vaccines.gov/basics/types
World Health Organisation. (2020, December) How do vaccines work?. https://www.who.int/news-room/feature-stories/detail/how-do-vaccines-work
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