University of Hong Kong Develop Next-Generation HIV Vaccine

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University of Hong Kong Develop Next-Generation HIV Vaccine

University of Hong Kong Develop Next-Generation HIV Vaccine

Recently, the Faculty of Medicine at the University of Hong Kong announced a major breakthrough with the development of the HIV vaccine pRhPD1-p27, which has achieved over six years of HIV prevention and virus control without the need for antiretroviral therapy.

pRhPD1-p27 is a type of PD-1-enhanced DNA HIV vaccine developed independently by the AIDS Research Institute at the University of Hong Kong. Compared to traditional vaccines, it has stronger immunogenicity and protective efficacy against viral infection. Animal studies have shown that monkeys vaccinated with the vaccine first experienced a peak in viral viremia after being attacked by a high dose of HIV, followed by a continuous decrease in viral load to undetectable levels.

Four monkeys in the study effectively suppressed the HIV virus in their bodies for two years without the need for antiretroviral therapy, and some monkeys remained without rebound for over six years. “The research results are encouraging and can be used in the future either alone or in combination with other strategies to treat HIV-infected individuals,” said Professor Chen Zhiwei, the lead researcher at the AIDS Research Institute of the University of Hong Kong.

In fact, with the advent of Highly Active Antiretroviral Therapy (HAART) in the late 20th century, AIDS is no longer a terminal illness and can even reach clinical indicators of “non-infectiousness,” with infected individuals having a lifespan close to that of the general population. At the same time, in recent years, the use of monoclonal antibodies in combination therapy has emerged. In a previous clinical trial, several HIV-infected individuals achieved complete HIV suppression two years after discontinuation of treatment.

“In recent years, various new treatment modalities for achieving functional HIV cure have emerged, many of which have entered the clinical trial stage, but a way to ‘completely control’ HIV has not yet been found,” Professor Lu Hongzhou, President of the Third People’s Hospital of Shenzhen, told reporters. The Third People’s Hospital of Shenzhen participated in the clinical trial study of pRhPD1-p27. “The main difficulties include drug resistance mechanisms, incomplete understanding of the HIV reservoir, and lack of effective strategies targeting the immune system.”

The road to developing an HIV vaccine is also difficult. With a development history of 40 years, three generations of development, and clinical trials repeatedly failing. Just last year, Johnson & Johnson announced that its highly anticipated HIV vaccine, “Mosacio,” had performed poorly in Phase III trials, leading to the discontinuation of clinical trials.

As of now, there are still dozens of HIV vaccine pipelines advancing globally. The vaccine needs to target specific sites, but HIV evades vaccines and immune system surveillance by continuously mutating. How far are we from completely conquering AIDS with the new generation of HIV vaccines? Reporters spoke with Professor Lu Hongzhou.

Reporter: For the past 40 years, hundreds of AIDS vaccines have entered clinical trials, but there have been no successful cases. What are the reasons?

Lu Hongzhou: Over the years, the development of AIDS vaccines has faced unique challenges compared to other infectious disease vaccines. First, HIV has extremely high genetic variability, with significant differences between different subtypes, making it difficult for vaccines to cover all forms of infection.

Furthermore, HIV has a strong ability to escape immune responses, evading attacks from the host immune system. For example, it can mutate rapidly in the body and hide within host cells, making vaccine design more challenging. Unlike other viruses, the immune system of the body is usually unable to effectively clear the virus after natural HIV infection, making it more difficult to effectively activate the immune system.

The lack of effective animal models also increases the difficulty of vaccine development. There is currently no animal model that can fully simulate HIV infection and vaccine effects, making clinical trials and vaccine evaluations more difficult.

The first generation of AIDS vaccines took traditional preparation routes such as inactivated viruses and attenuated viruses, stimulating the immune system to produce antibodies and T-cell responses.

With technological innovation, the current mainstream research track focuses on various technologies and platforms, including recombinant protein vaccines, viral vector vaccines, nucleic acid vaccines (including mRNA vaccines), and integrated vaccines. These technologies and platforms target different features and transmission modes of HIV, aiming to provide more effective prevention and control measures against HIV globally.

Reporter: Vaccines are divided into preventive and therapeutic types. Currently, where does the research on AIDS vaccines focus?

Lu Hongzhou: Currently, most of the research on AIDS vaccines focuses on preventive vaccines, which aim to prevent virus invasion and spread by producing antibodies and T-cell responses against HIV.

The second type is therapeutic control vaccines, which aim to activate the immune system, enhance the ability to eliminate the virus, or control the replication of the virus in the body, helping HIV-infected individuals slow down disease progression and reduce transmission risk.

The pRhPD1-p27, which is being researched in collaboration with our hospital, belongs to the “therapeutic vaccine” category, aiming to help the host clear the virus by enhancing host-specific immune responses to HIV.

Reporter: What are the main innovations and breakthroughs of pRhPD1-p27 compared to other AIDS vaccines?

Lu Hongzhou: pRhPD1-p27 is a “PD-1-enhanced DNA vaccine,” a new generation of vaccines that target dendritic cells (DCs). The main breakthroughs and innovations are in three aspects.

First, this vaccine is designed to express a fusion soluble PD-1, which binds to DC cells expressing the PD-1 ligand, efficiently recruiting antigen-presenting cells and enhancing antigen-specific CD4 and CD8+ T-cell immune responses.

Second, through machine learning, we have adopted a new “mosaic vaccine” design concept, screening out dominant antigenic epitopes. Among 539 HIV-1 strains, two mosaic p41 antigens targeting potential T-cell epitopes of 9 amino acids long, 70% achieved complete matching, and 96% achieved at least 7 amino acid matches. These antigens have a high coverage rate for potential T-cell epitopes in HIV-1 strains prevalent in China, theoretically inducing a broad spectrum of cross-immune responses.

There is also innovation in vaccine administration. In addition to traditional intramuscular injection, the use of electroporation nucleic acid drug delivery systems can instantaneously open the cell membrane of the tissue site to be delivered, directly delivering DNA into the cells.

It is worth mentioning that based on the PD-1-enhanced DNA vaccine technology platform, the University of Hong Kong is also developing DNA vaccines for various diseases, such as tumors.

Reporter: What does the data of “over six years of HIV infection prevention and control” in this study mean?

Lu Hongzhou: Successfully suppressing the virus for six years without the use of antiretroviral therapy indicates that these monkeys have achieved functional cure of HIV. This is an extremely encouraging result of animal experiments in the current field of HIV vaccine development.

However, it should be noted that there are differences between the immune systems of humans and non-human animals, especially in response to and replication processes of HIV. Animal models may not fully simulate the human immune system’s response to HIV.

So far, there have been no strictly controlled randomized clinical trials that have validated such levels of AIDS vaccines in large populations. Most candidate vaccines are mainly concentrated in mid-term (Phase II) and early (Phase I) studies, still some distance away from replicating similar effects in the human body. But this is

similar to that of the general population. Meanwhile, in recent years, the use of “monoclonal antibody combination therapy” has emerged. In a previous clinical trial, several HIV-infected individuals achieved complete suppression of HIV two years after stopping treatment.

“In recent years, various new treatment methods for achieving functional HIV cure have emerged, many of which have entered the clinical trial stage, but a way to ‘completely control’ HIV has not yet been found,” Professor Lu Hongzhou, President of the Third People’s Hospital of Shenzhen, told reporters. The Third Hospital of Shenzhen participated in the clinical trial research of pRhPD1-p27. “The main difficulties include drug resistance mechanisms, incomplete understanding of the HIV reservoir, and lack of effective strategies targeting the immune system.”

The road to developing an HIV vaccine has also been difficult. With a development history of 40 years, three generations of research and clinical trials have repeatedly failed. Just last year, Johnson & Johnson (J&J) announced that its highly anticipated HIV vaccine, “Mosacio,” performed poorly in Phase III trials, leading to the cessation of clinical trials.

To date, there are dozens of HIV vaccine pipelines progressing globally. Vaccines need to target specific sites, but HIV evades vaccine and immune system surveillance by constantly mutating. How far are we from a breakthrough with the new generation of HIV vaccines, and how far are we from completely conquering AIDS? Reporters spoke with Professor Lu Hongzhou.

Reporter: Over the past 40 years, hundreds of HIV vaccines have entered clinical trials, but there have been no successful cases. What are the reasons?

Lu Hongzhou: Over the years, the development of HIV vaccines has faced unique challenges compared to other infectious disease vaccines. Firstly, HIV has extremely high genetic variability, with significant differences between different subtypes, making it difficult for vaccines to cover all variants of the infection.

Secondly, HIV has a strong immune escape ability, which allows it to evade attacks from the host immune system. For example, it can mutate rapidly in the body and hide inside host cells, making vaccine design more difficult. Unlike other viruses, the immune system is usually unable to effectively clear the virus after natural HIV infection, making it more difficult to effectively activate the immune system.

The lack of effective animal models has also increased the difficulty of vaccine development. There is currently no animal model that can fully simulate HIV infection and vaccine effects, making clinical trials and vaccine evaluations more difficult.

The first generation of HIV vaccines followed traditional preparation routes such as inactivated viruses and attenuated viruses, stimulating the immune system to produce antibodies and T cell responses.

With technological innovation, the current mainstream development track focuses on various technical means and platforms, including recombinant protein vaccines, viral vector vaccines, nucleic acid vaccines (including mRNA vaccines), and integrated vaccines. These technologies and platforms target different features and transmission modes of HIV, hoping to provide more effective prevention and control measures for HIV globally.

Reporter: Vaccines are divided into preventive and therapeutic types. Where is the current focus of HIV vaccine development?

Lu Hongzhou: Currently, most of the HIV vaccines under development are preventive vaccines, which aim to prevent virus invasion and spread by producing antibodies and T cell responses against HIV.

The second type is the “therapeutic control” vaccine, which aims to activate the immune system, enhance the ability to eliminate the virus, or control the replication of the virus in the body, helping HIV-infected individuals slow down disease progression and reduce transmission risk.

The pRhPD1-p27 studied in our hospital belongs to the “therapeutic vaccine” category, which aims to enhance the host’s HIV-specific immune response, with the ultimate goal of helping the host clear the virus and achieve a cure for AIDS.

Reporter: What are the main innovations and breakthroughs of pRhPD1-p27 compared to other HIV vaccines?

Lu Hongzhou: pRhPD1-p27 is a “PD-1-enhanced DNA vaccine” that belongs to a new generation of vaccines targeting dendritic cells (DCs), with three main breakthroughs and innovations.

Firstly, this vaccine expresses a fused soluble PD-1, which binds to DC cells expressing PD-1 ligands, efficiently recruiting antigen-presenting cells and enhancing antigen-specific CD4 and CD8+ T cell immune responses.

Secondly, through machine learning, we have adopted a new “mosaic vaccine” design concept to screen for dominant antigenic sites. Among 539 HIV-1 strains, two mosaic p41 antigens targeting potential T cell sites of 9 amino acids in length achieved complete matching in 70% and at least 7 amino acid matching in 96% of the strains. These antigens have high coverage of potential T cell sites in HIV-1 strains prevalent in China, theoretically inducing a broad spectrum of cross-immune responses.

There is also innovation in vaccine administration. In addition to traditional intramuscular injection, an electric pulse nucleic acid drug delivery system is used to instantly open the cell membrane of the target tissue site to directly deliver DNA into the cells.

It is worth mentioning that based on the PD-1 enhanced DNA vaccine technology platform, the University of Hong Kong is also developing DNA vaccines for various diseases, such as tumors.

Reporter: What does the data of “over six years of HIV infection prevention and control” mean?

Lu Hongzhou: Successfully suppressing the virus for 6 years without the use of antiretroviral therapy indicates that these monkeys have achieved functional HIV cure. This is an extremely encouraging result in animal experiments in the current field of HIV vaccine development.

However, it should be noted that there are differences between the immune systems of humans and non-human animals, especially in response to and replication of HIV. Animal models may not fully simulate the human immune system’s response to HIV.

Currently, there have been no rigorously controlled clinical trials globally that have verified the ability of HIV vaccines to achieve such levels in a large population. Most candidate vaccines are mainly focused on mid-term (Phase II) and early (Phase I) research, and there is still a considerable distance from replicating similar effects in the human body. However, this is our ultimate goal.

Reporter: In addition to vaccines, what other explorations are being conducted at the Third People’s Hospital of Shenzhen for HIV infection prevention and treatment?

Lu Hongzhou: Achieving a “cure” or “functional cure” for AIDS is currently a hot and difficult issue in AIDS research. We have conducted multiple studies, such as exploring the key mechanism network and potential new targets of HIV latent infection, and have successively published multiple research results, providing new targets for the development of anti-HIV latent infection treatment strategies.

We have also established efficient latent activation screening for HIV-1 and clinical detection technology for the HIV-1 reservoir, greatly improving accuracy and sensitivity. In addition, through research, we have established an HIV reservoir-potential biomarker screening system and conducted in-depth research on the mechanism of HIV-1 latent activation.

For “functional cure,” our hospital has also led multiple clinical trials, including the combination of traditional Chinese medicine Gansuifen, PD-L1 antibody combined with sitafuran, and multifunctional M10CAR-T, for clinical research on HIV-1 latent reactivation.

Reporter: Looking at the global situation, how far have we progressed in preventing and completely controlling the progression of AIDS? How far are we from conquering AIDS?

Lu Hongzhou: Currently, the use of pre-exposure prophylaxis (PrEP) drugs has significantly reduced the risk of infection fornon-transmitting populations at risk of HIV.

For infected individuals, long-term HAART treatment has enabled many people to achieve near-normal lifespans. In the field of vaccines, several products have also entered clinical trials.

It is expected that in the future, the combination of PrEP and antiviral therapy will continue to be a major means of AIDS prevention and control. Both can work synergistically to minimize the risk of infection and control the disease. Monoclonal antibody combination therapy, especially long-acting virus control strategies, can maintain good virus control while reducing the frequency of administration, which is important for improving patient compliance and reducing the occurrence of drug resistance.

As for vaccines, given their tremendous potential to eradicate or significantly reduce the overall infection rate, they remain an ideal goal for AIDS prevention and control. Although widespread application has not yet been achieved, continued investment and research may lead to breakthroughs in the coming years.

Clinical trials of HIV functional cure still face difficulties, such as the lack of methods or markers to monitor and predict HIV-1 curative strategies and the lack of standards for safely conducting functional cure clinical trials. In the future, social, behavioral, and ethical research will also need to be included as part of clinical studies on HIV cure.

In conclusion, scientists need to continue to overcome difficulties to achieve comprehensive prevention and cure of HIV infections. With the development of science and technology and strengthened international cooperation, this goal is expected to gradually become a reality.

University of Hong Kong Develop Next-Generation HIV Vaccine