“At times I feel my body has been transformed into a factory of infection, a vessel of virus. The wheels and cogs are constantly turning, manufacturing more toxins and poisons. My body is merely the host”
– David B. Feinberg (American writer and AIDS activist)
Since the start of the HIV/AIDS epidemic, around 36 million people have died due to AIDS-related illnesses. Each year, thousands of children are born infected and often grow up to live a life of stigma. HIV, human immunodeficiency virus, is sexually transmitted and can also be transmitted to newborns during pregnancies. HIV often remains a silent killer and doesn’t show any symptoms during its latency state, which is when the virus is present in the body but it’s not producing more viral particles. The latency period can last up to 10 years in the absence of treatment as the virus infects important cells of the immune system such as T cells and macrophages and reduces their number in the body. On the surface of these cells, there exists a glycoprotein (CD4) that will interact with the proteins found on HIV, allowing it to fuse with the host cytoplasmic membrane and then destroy the immune cells. As a result, HIV will weaken the body’s natural defenses and damage the immune system, eventually causing acquired autoimmune deficiency disorder, also known as AIDS. The onset of AIDS is characterized by a blood CD4 cell count below about 200 per microliter where the body’s immune system is so depleted that a number of infections and cancers appear yet they would have been normally suppressed with an intact immune system. Although there are current antiretroviral treatments for HIV/AIDS, they are not equally distributed across countries and usually have difficult side effects. This explains the critical need for developing vaccines to protect our bodies against this deadly pathogen. The wait for the development of HIV vaccines is shared by scientists across many generations. Each day, thousands of researchers are trying to develop a vaccine that can limit the spread of the virus. It’s been exactly forty years since HIV was first spread and there is still not a single vaccine that has passed all three clinical trials. How could this be the case? Is HIV such a powerful microorganism that the efforts of thousands of brilliant minds can’t seem to halt its catastrophic spread? In this article, I will summarize some of the HIV vaccines that have undergone trials and why they have failed. Also, I will explore what makes HIV especially notorious at overcoming the immune response and why developing vaccines for it has been a daunting challenge.
It is important to note that viruses are not living things and cannot replicate on their own. They need a host cell that they can hijack and transform to support their metabolic activities and growth. Viruses pose a dangerous threat to our daily life and HIV is no exception. There are two types of HIV: HIV-1 (which is what 95% of patients are infected with) and HIV-2 which is usually less fatal. HIV is a retrovirus that attacks the person’s body system by targeting a specific type of white blood cells called the CD4 cells. The virus weakens the immune system and thus makes the person more susceptible to secondary infections caused by opportunistic pathogens, which explains the main cause of death from AIDS. It has also been shown that people infected with HIV have a higher chance of developing cancer. HIV is a challenging virus to defeat because it usually hides from the immune system in a group of CD4 lymphocytes, forming the HIV reservoir. In a way, HIV hijacks the CD4 cells and like any other virus, it uses these cells’ metabolic machinery in order to make new viral particles and infect other cells. HIV manages to inject the CD4 by using one of its proteins, the gp120, which fits with the CD4’s receptor (CCR4). A second protein (gp41) then attaches to a second receptor found on the CD4 cell (CCR5). After these connections have been established, the virus can thus enter the cell and start replicating. Since HIV is a retrovirus, meaning that its genomic material is RNA, not DNA, it will use its enzyme, reverse transcriptase, to transcribe its RNA to DNA. The reverse-transcribed HIV genome can then integrate itself within the host chromosomal DNA. It is important to consider that the RNA to DNA transcription process is rather sloppy and thus can make many mistakes, also known as mutations. It is precisely these mutations, and particularly the ones related to the virus’ surface envelope (made of glycoproteins), that allow HIV to gain new qualities which help it evade the body’s immune response or the drugs that target it. Because the viral epitopes in HIV are highly specific, mutagenic, and rapidly evolving, HIV can escape immune recognition such as camouflaging its outer envelope, making it extremely difficult to defeat.
Despite the challenges of defeating HIV, researchers have been trying to develop an effective vaccine that could prevent an HIV infection using various modifications and targets. The first vaccine that was developed dates back to November of 1986 and since then, more than 256 trials with over 44,000 healthy human volunteers have tested for a potential HIV vaccine. Vaccines allow us to develop an enhanced immune response to a specific virus by stimulating the production of antibodies. They do so by delivering small amounts of the dead/weakened virus or related proteins to the body which allows the production of antibodies and immune cells which will eventually neutralize the antigens (foreign molecules). As a result, the immune system remembers that specific pathogen and knows how to fight it in case you ever get infected with the real antigen in the future. Vaccines can stimulate the immune response in many ways.
The early vaccines intended to elicit an immune response by broadly neutralizing antibodies that target the HIV-1 envelope glycoprotein but various difficulties were encountered. Other HIV vaccines evolved to target the CD8+ T cells, yet this approach also yielded unsatisfactory results. As a result, various modifications have been made in order to reduce the challenges faced by previous vaccines. Researchers have decided to use a combination of broadly neutralizing antibodies as well as an efficient cellular response. It is evident that the types of HIV vaccines have diversified over the years, and with every meticulous alteration came a deeper understanding of how this dangerous virus works and the potential ways to combat its spread.
Some vaccine types include the live attenuated vaccines which use a weakened form of the virus while others include inactivated viral vaccines which use the dead version of the virus. Other types of HIV vaccines have been researched including protein vaccines, DNA vaccines, and viral vector vaccines. HIV protein vaccines, or peptide vaccines, are made of similar proteins that HIV possesses. This triggers the B cell and T cell-mediated immune response in case he/she/they ever get infected with the virus at some point. DNA vaccines, as their name implies, use HIV’s genes that correspond to similar proteins found in the virus to induce the body’s immune system to fight these proteins once the person gets infected with HIV. On the other hand, viral vector vaccines utilize a vector (a harmless virus) that acts as a cargo to deliver HIV genes to our body cells. A promising viral vector vaccine is the canarypox viral vector. This virus is known to cause disease in birds but not in humans thus utilizing it has been proven to be safe. This vaccine was also used in combination with RV144 which is a protein vaccine tested in Thailand and showed promising results such as preventing some HIV infections.
Unfortunately, as we all know, there is currently not a single HIV vaccine that has passed all the clinical trials needed to be approved for use. More recently, Johnson & Johnson underwent their Phase 2b Imbokodo trial in 2017 with 2,637 cisgender women as participants from five different countries. The study utilized an adenovirus 26-based mosaic vaccine which delivers the HIV antigen (a protein that stimulates an immune response) that was proven to be effective in Ebola as well as COVID-19. The mosaic vaccine includes several immune-stimulating proteins, the mosaic antigens, which are encoded by the genes of different HIV strains. These antigens are stored within the adenovirus serotype 26 (Ad26), a disabled cold virus. It is in fact not the platform itself that induces the protection but rather the immune response to the antigen in the platform. During the Imbokodo clinical trial, the participants were offered pre-exposure prophylaxis medication to prevent HIV infections. The participants were randomly distributed into two groups: those who received the placebo and those who received four vaccinations for a period of one year in addition to an adjuvanted HIV protein (clade C gp140) to boost their immune response . Disappointingly, in August of 2021, J&J announced that the vaccine did not provide the needed protection against HIV infection in women who are at high risk of HIV infection in sub-Saharan Africa. In fact, the vaccine only had a 25% efficacy rate which is too low to be approved for use, however, it was still proven to be safe. In parallel to the Imbokodo trial, the J&J’s Phase 3 Mosaico (HVTN 706/HPX3002) study, which started in 2019, aims to test the efficacy of a different vaccine in various participants such as men who have sex with men (MSM) and transgender individuals in North America, South America, and Europe. This vaccine is designed to utilize a mixture of four adenovirus serotype 26 vectors in combination with several proteins. Both vaccine studies utilize an adenovirus that acts as a harmless vector to deliver the HIV genes, provoking an immune response due to the translation of the engineered genes to HIV proteins (mosaic antigens). The Phase 3 Mosaico study is still ongoing and is expected to be completed in March 2024. Although the Imbokodo trial did not yield sufficient efficacy, it has provided great insight to the field of Immunology, serving as a landmark for future vaccine trials that will undoubtedly learn from its limitations.
Other potential HIV vaccines include mRNA vaccines and their importance has been well-observed in the development of the current COVID-19 vaccines. Moderna, a well-known pharmaceutical company for mRNA therapeutics which also produced a COVID-19 vaccine, is currently starting its trial for two HIV vaccines, the mRNA-1644, and mRNA-1644-v2-Core. Like any other mRNA vaccines, these two vaccines aim at injecting the RNA, which carries the code for the HIV antigen, and thus stimulates the immune response to produce antibodies against the virus. Once the B lymphocytes are primed to target that specific antigen, they will become more effective in fighting the virus if a person ever gets infected with HIV. The Moderna HIV vaccine trial is expected to be completed in the spring of 2023 and its potential lies in combating the major limitation faced by HIV vaccines: inducing the production of neutralizing antibodies. There are currently several other vaccines undergoing trials and their results are highly anticipated in hopes of reaching a high enough efficacy rate to finally combat HIV.
While vaccines aim at preventing the spread of the virus and equipping the immune system to fight off the pathogen, it is also important to consider the antiviral drugs that help in controlling the symptoms of patients already infected with HIV. HIV medicines, also known as antiretroviral therapy (ART) are used to control the infection but they do not ultimately cure the patient. Antiretroviral therapy drugs aim at inhibiting key survival mechanisms of HIV. They are divided into several classes and some of them include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and fusion inhibitors. Nucleoside reverse transcriptase inhibitors (NRTIs) work by blocking reverse transcriptase thereby preventing HIV from replicating. The NNRTIs physically prevent the reverse transcriptase from working by directly binding to it. Moreover, protease inhibitors block the protease enzyme that is responsible for the maturation of the virus while fusion inhibitors block the fusion of HIV with the host cell’s membrane which prevents it from infecting cells. To prevent HIV, pre-exposure prophylaxis (PrEP) can be taken to reduce the risk of being infected. These antiviral therapies must be taken consistently or otherwise, they will eventually lead to drug resistance, making HIV even more prone to develop mutations and as a result, much more difficult to fight. One of the problems faced by antiviral drugs is that they can induce side effects and are not accessible and available across nations, especially in developing countries. This highlights why developing HIV vaccines is extremely crucial for reducing the spread of the virus. As of November 18, 2021, a new antiretroviral treatment (cabotegravir with rilpivirine) has been approved by NICE (National Institute for Health and Care Excellence) for controlling HIV infections and decreasing the viral load, paving the way for less toxic modern HIV treatments.
In conclusion, the development of effective HIV vaccines has been a daunting challenge due to the mechanism by which HIV can evade the immune system and escape recognition. You might be wondering about what we can currently do to decrease the spread of HIV/AIDS. Firstly, it is crucial to focus on the importance of sexual health education through having open discussions with professional health experts to make the topic less of a taboo. Not only do patients have to deal with the health complications that come with HIV/AIDS but they also have to face the terrible stigma that accompanies this disease, making it even more difficult to lead a healthy life. Thus, it is important to encourage testing and raise awareness about the virus and its disease, especially in developing countries. Moreover, there should be a global focus on expanding access to antiretroviral drugs since third-world countries often do not have access to these medications. Despite the fact that we currently don’t have an effective and safe vaccine for HIV, there exists collective anticipation towards halting HIV infections in the future. The various vaccines that have undergone trials and failed do not represent an end to the journey but rather, a stepping stone within the scientific field. The road towards HIV vaccines is a long and tiresome one yet this has fueled researchers with the will to keep moving forward, to revolutionize current therapeutic measures and biotechnologies, and to push against all odds and challenges. It is precisely the failure of past vaccines that highlights a key value in science: to learn from the mistakes of previous scientists and to build upon them for the sake of our current and future generations.
Edited by Mohamad Wehbe