The Future of HIV Vaccine Development, Learned Lessons from COVID-19 Pandemic

Abstract

With nearly 13 million new HIV infections in 2022, it is imperative that as many preventive options be available to those most at risk. Without doubt, an effective vaccine would be a game changer, and despite the disappointments and challenges, the development of an effective HIV vaccine should remain a priority. The past few years have been tough for HIV vaccine research, with several high-profile trials being stopped early and others having negative results. With every setback, however, there are lessons to be learned. Neutralizing antibodies (bnAbs), either by giving infusions of bnAbs or by eliciting the immune system to generate its own, are the main emphasis. The focus seems to be on the development of mRNA vaccine approaches using technologies pioneered during the development of COVID-19 vaccines. mRNA platforms are being used in many of the current phase 1 vaccine studies. The quick development of mRNA vaccines for COVID-19 will likely not be repeated with HIV, which is a much more formidable immunological foe than SARS-CoV-2. However, it is reassuring that vaccine trials are moving to sub-Saharan Africa, and large mRNA manufacturing facilities are being planned for the region.

1. Introduction

The expeditious development and implementation of COVID-19 immunizations within a span of less than a year is a remarkable accomplishment in the realms of science, medicine, and public health. The rapid progress observed in this development was built upon extensive research and technology developments in the field of HIV/AIDS spanning several decades. The ongoing pursuit of an HIV vaccine aimed at effectively eradicating the HIV pandemic has thus far yielded inconclusive results. In this analysis, we leverage the knowledge and insights of the official organizations to underscore significant lessons learned from the progress made in the development of the COVID-19 vaccine. These lessons include the importance of fostering collaborations between public and commercial entities, ensuring the inclusive involvement of individuals impacted by the infectious pathogen, and maintaining consistent funding for fundamental research. In this chapter, we present a comprehensive overview of key considerations in developing a revised and accelerated approach toward the development of a reliable and efficacious HIV vaccine.

As we contemplate the significant progress made in the field of treatment and prevention in light of the COVID-19 pandemic, we find ourselves in a favorable position to amalgamate and implement the knowledge acquired to address other worldwide infectious disease crises. Both HIV and COVID-19 are examples of newly discovered viruses that initially lacked specialized diagnostic tests, therapies, or preventative methods. As a result, the first approach to containing these viruses relied heavily on the public’s adherence to behavioral modifications in order to reduce the spread. Both infections are classified as RNA viruses and possess the inherent ability to undergo mutations and diversification, hence posing significant challenges in the development of effective therapies. Moreover, the COVID-19 pandemic has brought attention to the enduring risks and susceptibilities of the public health infrastructure, encompassing the consequences of persistent health disparities and the marginalization of disadvantaged populations. Vulnerable populations residing in challenging social circumstances have disproportionately borne the weight of both COVID-19 and HIV, as these factors impede effective disease prevention measures (Figure 1).

Figure 1.

Components of SARS-CoV-2 and HIV viruses. Components of SARS-CoV-2 and HIV. A schematic representation of SARS-CoV-2 (left) and HIV (right) is shown, along with key structural components (Figure adapted from [1]).

Over the course of more than four decades, extensive research and financial resources have been dedicated to the investigation and advancement of HIV vaccine research. These endeavors have yielded valuable insights, indicating that an all-encompassing prevention strategy should be both comprehensive in nature and guided by empirical evidence.

In a manner akin to the preventive measures employed for COVID-19, the prevention strategies for HIV can be broadly classified into three primary domains: behavioral modifications, biological advancements, and mitigation of structural impediments. Both diseases can be effectively controlled by using prevention strategies that have the capacity to considerably decrease transmission rates and hence lower the number of new infections. This is crucial in managing a pandemic.

The Division of AIDS of the National Institute of Allergy and Infectious Diseases recently organized a workshop titled “Utilizing the COVID-19 Experience to Expedite the Advancement of a Secure and Effective HIV Vaccine.” The objective of this workshop was to evaluate how the lessons learned from the COVID-19 pandemic can be applied to expedite the development of an HIV vaccine. Based on the workshop, a number of strategies were identified as crucial for expediting the development of an HIV vaccine. These strategies include the adaptation of both basic and clinical science approaches, enhancing collaborations between various US government agencies and public-private partnerships, and revitalizing the research community’s dedication to involving and connecting with diverse communities that are disproportionately affected by the HIV pandemic. This Perspective article centers on the COVID-19 reaction implemented by the United States government and explores the potential application of the lessons derived from this experience to the HIV pandemic.

2. How did the progress made in HIV research lay a foundation for the subsequent study conducted on COVID-19?

In order to examine the potential application of the COVID-19 experience to HIV, it is imperative to acknowledge that the achievements and expedited progress in the creation of COVID-19 vaccines were primarily facilitated by extensive research conducted on HIV over the course of several decades. Several significant contributions have been made in the field, including the development of novel methodologies for the rapid identification and sequencing of emerging viral diseases. Additionally, advancements have been made in vaccine delivery methods, such as the utilization of nucleic-acid-based mRNA vaccines and adenovirus vector vaccines. Furthermore, the development of a stabilized spike protein for COVID-19 was partially facilitated by the extensive investment in research on the structural biology of HIV over the course of several years. The field of HIV vaccine research has also established a well-developed clinical trial infrastructure, which is backed by the National Institutes of Health (NIH). This infrastructure allows for prompt access to knowledgeable scientific specialists and extensively trained clinical personnel. Additionally, it demonstrated the significance of cultivating connections between the academic and industrial sectors. This collaboration had a crucial role in enhancing the capabilities of healthcare systems, both domestically in the United States and on a global scale. This was achieved by creating clinical trial sites, particularly in regions with limited resources, thereby expanding the international presence of the organization. However, there is still a significant amount of work that must be undertaken in order to enhance worldwide accessibility to vaccinations and other preventative measures. This can be achieved through the equitable sharing of intellectual property and facilitating the manufacturing and distribution processes on a global scale. Significantly, the extensive duration of active community involvement in HIV research has played a crucial role in providing valuable insights to COVID-19 vaccine developers and clinical site personnel regarding effective strategies to engage and connect with the groups who are disproportionately affected and underserved.

The research on the development of a vaccine for HIV has already reached its fifth decade [2]. The development of a safe and effective HIV vaccine has proven to be challenging, with numerous obstacles. However, scientists are currently in a favorable position to leverage the knowledge and insights gained from the development of the COVID-19 vaccine. So far, there has been only one HIV-1 vaccine effectiveness trial conducted, known as RV144, which has demonstrated a moderate decrease in HIV acquisition [3]. No evidence of protection against infection was shown in a second experiment, known as HVTN 702, which utilized a vaccine design that was theoretically identical to the one being evaluated [4]. In contrast, the HVTN 705 trial did not demonstrate any observable protective effects, despite the fact that it employed a vaccine with a distinct conceptual framework [5]. To date, a total of seven HIV-1 vaccine effectiveness studies have been conducted, of which six had no significant efficacy. Additional significant strategies for HIV prevention encompass the implementation of therapeutic interventions aimed at reducing viral loads to levels below the threshold necessary for transmission. Furthermore, the administration of pre-exposure prophylaxis through oral, injectable, or vaginal ring methods, utilizing potent and long-lasting antiretroviral agents, serves to impede the establishment of viral infection. Lastly, the passive delivery of broadly neutralizing antibodies represents another noteworthy approach in the prevention of HIV transmission [6]. Nevertheless, the successful implementation of these interventions is contingent upon adherence, a task that proves to be difficult in environments characterized by prevalent stigma or limited access due to logistical, financial, or other barriers. It is our contention that the sole assurance of a prolonged cessation of the AIDS pandemic is contingent upon a fusion of preventive measures that do not rely on vaccines, as well as the creation and implementation of an HIV vaccine that is both safe and adequately efficacious. There has been no waste of time or money in the decades-long search for an effective HIV vaccine. In fact, the knowledge gained along the way has been crucial in creating vaccinations to protect against the unique, global SARS-CoV-2 pandemic. We relate the actual history of HIV vaccine research, complete with dead ends and setbacks, to better explain where antiviral vaccines are at this time. The research and development of HIV was shown to have more of an indirect impact. The recurrent failures of HIV vaccine candidates in phases 2 and 3 of clinical trials have, in reality, been a crucial spur for the development of viable vaccine technologies in the present day. We contradict the claim that efforts to produce an HIV vaccine have been a dead end, and we show that the COVID-19 vaccines generated recently are the direct offspring of vaccines that have been shown to be effective against Ebola, MERS, and SARS. These effective vaccinations owe a great deal to the ups and downs of HIV vaccine research and development, as well. Finally, we explore what we may learn from the HIV vaccine development setbacks about how to modify SARS-CoV-2 vaccines to prevent immune evasion by new variations. Finally, we discuss the possibility of a “reverse spillover effect” between the progress made on SARS-CoV-2 vaccines and the work done on an HIV vaccine (Table 1).

Vaccine Model	SARS-CoV-2 Candidates	HIV Vaccine Progenitor	Reference
Purified Viral Subunit	47	AIDS VAX	[7]
Nucleic Acid	40	HVTN 505	[8]
Viral Vector	23	Merck STEP	[9]

Table 1.

HIV vaccine progenitors in clinical trials.

HIV vaccine progenitors of SARS-CoV-2 vaccine candidates in clinical trials.

The continuous and substantial allocation of resources toward fundamental scientific research.

The areas of HIV and COVID-19 vaccines have a mutually beneficial relationship, wherein insights gained from the HIV field have contributed to the development and evaluation of COVID-19 vaccines. These advancements, in turn, have the potential to inform the design of HIV vaccines. The utilization of structural biology in the field of vaccine design is clearly apparent. Several COVID-19 vaccines have utilized a stabilized version of the spike protein, which has been developed through a series of advancements inspired by HIV, respiratory syncytial virus, and other coronaviruses such as severe acute respiratory syndrome–associated coronavirus (SARS-CoV) and Middle East respiratory syndrome–associated coronavirus (MERS-CoV) [10]. Considering the achievements in the realm of structure-based vaccine design, it is plausible for the HIV domain to incorporate insights derived from COVID-19 and other viruses that possess a trimeric glycoprotein functioning as a type I fusion protein, facilitating the fusion between the virus and host cells. Nevertheless, the HIV Envelope (Env) protein presents distinct hurdles in comparison to its counterpart in other viruses. Several factors contribute to the challenges in developing an effective vaccine against HIV. These factors encompass the existence of a compact and inadequately immunogenic glycan shield on the Env protein, the occurrence of molecular mimicry of Env epitopes that elicit cross-reactivity of antibodies with human proteins, and the presence of variable loop regions in Env that exhibit epitopes of highly effective neutralizing antibodies. Additionally, the stabilized HIV Env spike displays non-neutralizing or weakly neutralizing antibodies [11, 12]. Furthermore, it is often observed that unmutated forms of broadly neutralizing antibodies (bnAbs), also known as “germline” versions, do not exhibit binding affinity toward the majority of Env proteins. As a result, either the development of tailored germline-targeting compounds or meticulous selection of immunogens is necessary to activate a bnAb response [13]. Moreover, HIV-1-bnAbs exhibit atypical characteristics, including autoreactivity, elongated third heavy chain complementarity determining regions, and a high prevalence of uncommon somatic mutations. These distinctive qualities contribute to the scarcity of bnAb precursors due to immunological tolerance deletion or their challenging activation.

The examination of the development of HIV neutralizing antibodies during ontogeny indicates that the creation of a successful vaccine will probably necessitate the administration of various immunogens in a precise sequence to assist the appropriate generation of antibodies [14]. The HIV envelope presents additional intricacies that are distinct to this virus. These complexities encompass the extensive sequence variability observed worldwide, the incorporation of the viral genome into host cells, the prolonged period of asymptomatic infection, and the absence of spontaneous remissions [15]. Therefore, the development of an HIV vaccine is a challenging task that necessitates further scientific exploration and ongoing monitoring of viral strains. This is because the immune responses required to elicit protection against currently prevalent strains must be distinct in nature from those generated by natural infection.

Several significant contributions made by the existing HIV Vaccine Trials Network (HVTN) were utilized in the endeavor to develop a vaccine for COVID-19. In the context of COVID clinical laboratory operations, it was seen that the network possessed established immunology assays and quality assurance procedures for HIV that were compliant with regulatory standards for product licensure. These existing resources may be readily adapted for the development and evaluation of COVID-19 vaccines [16, 17]. The utilization of standardized binding assays in conjunction with SARS-CoV-2 proteins and neutralization assays involving pseudo-viruses or replication-competent viruses facilitated the evaluation of different vaccine platforms. This approach provided valuable insights into the optimal dosage, administration schedules, and efficacy of COVID-19 vaccines by analyzing antibody responses [18]. These tests have also furnished scientists with the means to expeditiously evaluate vaccination reactions and potential efficacy against the various emerging variations of concern over the course of the pandemic. While a significant amount of attention has been directed into the study of antibodies in the context of vaccine development and immune surveillance, the investigation of T cells has received comparatively less emphasis. The evaluation of vaccine-induced T-cell responses by standardized assessments was predominantly restricted to phase 1–2 studies due to the challenges associated with obtaining peripheral blood mononuclear cells from patients involved in the extensive COVID-19 trials. Nevertheless, an increasing body of evidence indicates that the involvement of T cells in the immunological response of the host is necessary for providing early, comprehensive, and long-lasting defense against SARS-CoV-2, particularly when confronted with novel variations of concern [19, 20]. Significantly, the utilization of standardized assays enables researchers to establish immune correlates of protection, facilitating the comparison of data across studies where direct demonstration of effectiveness is challenging and time-consuming. This is particularly relevant when testing a vaccine in new populations or following dose modifications or manufacturing changes [21]. The applicability of this approach to the HIV vaccine domain is noteworthy, given the identification of HIV-1 risk correlates that involve multiple immune responses in the RV144 HIV-1 vaccine efficacy trial [22]. However, it is important to note that these correlates have not yet been established as protective factors, as they have not been validated in another vaccine efficacy trial. The identification of a correlate of protection for HIV has proven to be a more formidable task compared to that of COVID-19. The hypothesis that the presence of antibodies against the spike protein, whether acquired through natural infection or vaccination, serves as a correlate of protection against COVID-19 is substantiated by various lines of evidence [23]. These include supporting evidence for a mechanistic correlate of protection, which can be inferred from experimental challenge studies involving the passive transfer of antibodies, as well as from investigations involving human monoclonal antibodies [24, 25, 26].

Therefore, further research is required to enhance the understanding of human immunology in tissue sites beyond the bloodstream, pertaining to both HIV and SARS-CoV-2.

The replication of the SARS-CoV-2 virus in blood is not substantial. The virus predominantly targets epithelial cells located on mucosal surfaces within the nasal cavities, oral-pharyngeal spaces, and lungs, thereby minimizing exposure to the systemic immune system [27]. At present, there is limited understanding on the participation of antigen-specific CD8 T cells, memory B cells, or released antibodies in these three locations in humans due to the challenges associated with acquiring specimens. In a similar vein, distinct immune reactions to HIV have been observed in several bodily compartments, including the blood, gastrointestinal system, genital tract secretions, and tissues. These findings suggest that mucosal responses play a crucial role in effectively preventing the transmission of HIV-1 through sexual encounters. The levels of serum antibodies and mucosal antibodies after the administration of a broadly neutralizing anti-HIV antibody through intravenous infusion have been observed to be lower in the mucosa compared to the serum. This finding suggests that the effectiveness of the antibody in preventing infection in tissue may differ from its effectiveness as measured in peripheral blood [28]. Therefore, the examination of blood as a substitute for assessing mucosal immune responses may provide a notable constraint due to potential inadequacies in capturing the magnitude and efficacy of vaccine-induced immune responses and the transfer of antibodies in the mucosal region.

In the future, the incorporation of evaluations pertaining to mucosal tissue and secretions into comprehensive assessments will establish a foundation for the advancement of novel vaccines aimed at the prevention of viral infections.

The viral dynamics of SARS-CoV-2 and the level of protection provided by vaccines differ across different tissue compartments, leading to varying clinical outcomes in terms of protection against asymptomatic or mild/moderate illness compared to severe disease and mortality. The presence of both natural immunity resulting from SARS-CoV-2 infection and immunity produced by vaccination has not effectively halted the formation and swift dissemination of viral variations, including the highly transmissible delta variant (B.1.617.2).

The aforementioned varieties include the delta (B.1.617.2) and omicron (B.1.1.529) variants. The duration of protective immunity and its potential to inhibit the formation of immunological escape variations remains uncertain. There is a requirement for a collaborative research endeavor to examine the efficacy and longevity of immune responses to SARS-CoV-2 and HIV in human subjects following both spontaneous infection and the administration of vaccinations.

One significant insight gained from the COVID-19 pandemic is the safety and efficacy of mRNA vaccines in generating a strong immune response to symptomatic disease. However, it is important to note that these vaccinations offer limited protection against infection. The utilization of this technology has numerous advantages in the development of an HIV vaccine; however, it also entails certain constraints that necessitate careful consideration (Table 2).

Benefits of mRNA vaccines	Limitations of mRNA vaccines
Fast development timeline	mRNA instability
Affordable production	Ultra-cold chain storage and transportation need
Adjuvant not needed	Uncertainty of immunogenicity and durability
Protein purification not required
Enables delivery of complex immunogens

Table 2.

Benefits and limitations of mRNA vaccines.

The mRNA vaccine technology presents several benefits and limitations that should be considered in designing future HIV mRNA vaccines.

The durability of mRNA COVID vaccines has been observed to potentially extend for several months or even longer when administered with booster doses. Numerous disciplines within the realm of infectious diseases, such as HIV research, are currently expediting their investigations utilizing this innovative technique. In the field of HIV research, there is a potential to efficiently develop vaccines for various HIV antigen configurations, including complicated tri-membrane stabilized trimers. These vaccines can be utilized to enhance regimen techniques, such as sequential immunization [29]. Considering the ability of developers to efficiently generate GMP (Good Manufacturing Practice) material for mRNA vaccines, at a reduced cost compared to conventional approaches, it is plausible that this technological advancement could facilitate the acceleration of preclinical and clinical testing processes. Furthermore, the utilization of the mRNA platform has the potential to provide a series of sequential clinical trials for HIV, wherein the immunogen can be gradually constructed, enhanced, and optimized in order to elicit the intended clinical outcomes. Moreover, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has launched a Phase 1 clinical trial evaluating three experimental HIV vaccines based on a messenger RNA (mRNA) platform, a technology used in several approved COVID-19 vaccines. NIAID is sponsoring the study, called HVTN 302, and the NIAID-funded HIV Vaccine Trials Network (HVTN), based at Fred Hutchinson Cancer Research Center in Seattle, is conducting the trial [30].

Adjuvants are essential constituents of vaccines and serve a vital function in enhancing the immune response. The COVID-19 pandemic has provided evidence of the efficacy and safety of innovative adjuvants, including the TLR7/TLR8 agonist found in COVAXIN® and saponin adjuvants utilized in Novavax-CoV2373. Considering the swift accumulation of safety data derived from clinical trials and subsequent implementation of these adjuvants for COVID-19 vaccines, it is now feasible to employ these innovative adjuvants for the development of vaccines targeting HIV and other infectious pathogens. In addition, noteworthy findings were seen regarding the safety and effectiveness of the COVID-19 spike nanoparticle vaccine [31]. This vaccine, incorporated inside the Novavax vaccine, stands as the sole nanoparticle platform to have received Emergency Use Authorization (EUA) thus far. The efficacy of these nanoparticles in enhancing the establishment and sustained presence of germinal centers following immunization has been demonstrated.

Nanoparticles have demonstrated potential utility within the realm of HIV vaccine research. The validation of the germline-targeting concept was conducted in the G001 study by the International AIDS Vaccine Initiative. This study utilized a self-assembling nanoparticle composed of engineered HIV Envelope proteins that were connected to a spherical protein structure. The results of the study demonstrated that the immunogen was capable of stimulating naive B cells, which are responsible for producing precursors to a specific category of broadly neutralizing antibodies [32].

Positive first-in-human trial results have highlighted potential of a nanoparticle vaccine toward broadly neutralizing against HIV. Researchers have characterized robust T-cell responses in volunteers participating in a Phase I trial for a self-assembling nanoparticle HIV vaccine. The results, published in Science Translational Medicine, are a major step in the development of a vaccine for overcoming the HIV/AIDS epidemic [33].

In the subsequent phase, scientists affiliated with the National Institutes of Health (NIH) are actively involved in establishing collaborations between public and private entities. The objective of these partnerships is to create and evaluate multiple mRNA-based vaccines that employ a similar methodology to activate various untapped B cells. This includes a vaccination regimen that utilizes a germline-targeting initial dose followed by a booster, with the aim of eliciting broadly neutralizing antibodies against the human immunodeficiency virus (HIV). This particular initiative is registered under the clinical trial identifier NCT05001373. Furthermore, an ongoing initial human trial is currently assessing the potential of utilizing an mRNA platform to deliver soluble or membrane-bound HIV Env trimers as a viable approach for expeditious and iterative development of HIV vaccines (NCT05217641).

Research on COVID-19 is also demonstrating significant progress in various domains of vaccine research, which has the potential to propel the creation of an HIV vaccine. The wide range of clinical and point-of-care diagnostic kits available for COVID-19 have played a vital role in monitoring the spread of the virus and identifying the necessity for infection prevention and control measures, thereby effectively preventing transmission. The utilization of testing data has the potential to inform and shape clinical and public health policies in a meaningful manner. Additionally, closely monitoring testing data throughout clinical trials can enhance the efficiency of study design. The HIV field stands to gain advantages from the use of more streamlined testing methods. However, it is important to acknowledge that there exist significant distinctions between HIV and SARS-CoV-2, necessitating the utilization of tests in distinct manners. For instance, the occurrence of vaccine-induced seropositivity (VISP) resulting from an HIV vaccine does not imply the presence of immunity against infection.

Indeed, the implementation of Vaccine-Induced Sero-Positivity (VISP) presents an additional challenge that may potentially contribute to stigmatization. This issue arises from the necessity to differentiate between the immunological response triggered by vaccination and that caused by infection. Consequently, an extra nucleic-acid test is required to confirm the presence of an infection. If left unattended, this particular difficulty has the potential to lead to erroneous HIV diagnoses, subsequent negative social consequences, and false reporting to health agencies.

In order to differentiate between antibodies induced by HIV infection and antibodies induced by an HIV vaccine, it is necessary to know which antigens were included in the vaccine(s) and to have assays set up to allow for this distinction. This is often not the case in routine diagnostic settings. In sub-Saharan Africa, HIV diagnosis relies mainly on the detection of antibodies to HIV using rapid diagnostic tests (RDTs). To improve the accuracy of HIV diagnostic algorithms, two to three RDTs are used in series or in parallel as screening, confirmatory, or tiebreaker tests. Considering the emotional trauma and social harms caused by HIV misdiagnosis, it is imperative that the RDT-based diagnostic strategies are able to discriminate HIV antibodies elicited by vaccination from those generated in response to an infection [34].

3. Public-private collaboration and partnerships

The COVID-19 pandemic has demonstrated the potential outcomes that can be achieved when there is a pressing demand for collaborative efforts. The magnitude of the COVID-19 threat necessitated coordination across many agencies in the United States to prevent redundant actions, foster potential collaboration, and address detected deficiencies. This collaborative endeavor, known as the Countermeasures Acceleration Group (CAG), sprang from the first initiative called Operation Warp Speed (OWS), with a focus on unity in mission, a shared vision, and the pursuit of common goals. In a manner reminiscent of the Manhattan Project, a significant scientific endeavor that led to the creation of nuclear weapons and expedited the conclusion of World War II, the present initiative represents a collaborative effort involving governmental entities such as the Departments of Health and Human Services, Defense, and various other federal agencies. This endeavor also encompasses the active participation of academic institutions and private enterprises, thereby establishing a public-private partnership. The Office of the Assistant Secretary for Preparedness and Response (ASPR) and the COVID-19 Vaccine Acceleration Group (CAG) collaborated to enhance ongoing initiatives within the Department of Health and Human Services (HHS) aimed at expediting the progress, production, and dissemination of vaccines, treatments, and diagnostics for COVID-19.

The organizational structure known as OWS/CAG facilitated the integration of centers of excellence across various teams of the US government. This structure also enabled the utilization of the skills and strengths of each entity involved in achieving the primary objectives of the framework. The National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID) possess extensive expertise in the planning and implementation of Phase 3 clinical studies on a significant scale. Through the establishment of strong collaborative relationships in the fields of HIV, influenza, and other respiratory diseases, the NIH/NIAID successfully transitioned their efforts toward performing effectiveness trials for COVID-19 vaccines. The pivot was able to utilize the clinical research networks created by the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious illnesses (NIAID) for HIV and other infectious illnesses. This was done in order to develop the COVID-19 Prevention Network (CoVPN) and effectively respond to the urgent demand for vaccines and monoclonal antibodies (mAbs) targeting SARS-CoV-2. The CoVPN consists of several organizations that have received funding from the National Institute of Allergy and Infectious Diseases (NIAID). These organizations include the HIV Vaccine Trials Network (HVTN), the HIV Prevention Trials Network (HPTN), the AIDS Clinical Trials Group (ACTG), and the Infectious Disease Clinical Research Consortium (IDCRC).

Moreover, the establishment of the accelerating COVID-19 therapeutic interventions and vaccinations (ACTIV) public-private collaboration aimed to facilitate the coordination of a research approach that focuses on prioritizing and expediting the advancement of the most viable treatments and vaccinations. The faster assessment of grants, contracts, agreements, and reporting of results required for the implementation of life-saving measures was facilitated by the coordination of resources, flexibility of established systems, and a collaborative approach across many federal agencies, including the National Institutes of Health (NIH).

It is imperative to harness a comparable culture characterized by a sense of urgency and a drive to expand the pool of possible collaborators, encompassing both public and commercial entities, in order to effectively facilitate forthcoming research endeavors pertaining to the development of an HIV vaccine.

Ensuring consistent evaluation and comparability of vaccination products was of utmost importance, necessitating harmonization across all Phase 3 vaccine efficacy investigations. The National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID) played a significant role in the establishment and organization of a unified and autonomous Data and Safety Monitoring Board (DSMB). This board was responsible for ensuring the safety of all COVID-19 vaccination studies financed by the United States. Moreover, the utilization of immunological assays that have been approved and financially supported by the National Institutes of Health (NIH) facilitated the comparison of outcomes among various vaccine platforms and facilitated the identification of factors associated with protection. The Centers for Disease Control (CDC) collaborated with other authorities to make necessary preparations and facilitate the distribution of authorized and available vaccines. Furthermore, the Biomedical Advanced Research and Development Authority (BARDA), a division of the Department of Health and Human Services (DHHS), effectively employed the public-private partnership (PPP) framework in the initial stages of the pandemic response. This was achieved by enhancing outreach initiatives and reducing the risks associated with product development for industry collaborators. BARDA accomplished this by entering into contracts that provided both research and manufacturing support, along with the necessary flexibility and funding. Public-private partnerships (PPPs) have successfully facilitated collaboration between academics, industry, and financing agencies, by integrating public sector commitments with skilled partners in product and business development. This collaboration aims to enhance the overall health of people. The enhancement of public-private partnerships (PPPs) in vaccine research can be bolstered through the implementation of adaptable governance and funding mechanisms that are designed to facilitate the advancement of product development within the PPP framework. An instance of the utilization of the Other Transaction Agreement (OTA) method by BARDA is seen, whereby flexible portfolio-based funding is employed. This approach involves collaborative decision-making between partners about the inclusion and exclusion of candidates in the portfolio, taking into consideration factors such as product performance, technical risk, and programmatic requirements. The United States government additionally undertook financial risk by expanding manufacturing in tandem, prior to the availability of vaccination efficacy evidence to substantiate the continued clinical study. The utilization of the advance purchase agreement model played a crucial role in reducing the duration required for the development of medical countermeasures. The COVID-19 pandemic necessitated the utilization of these financial structures, which played a crucial role in enabling flexibility within the Public-Private Partnerships (PPPs). As a result, substantial savings in terms of time, effort, and costs were achieved.

The engagement between several governments and the corporate sector to advance multiple COVID-19 vaccine candidates was of equal importance.

The success of these cooperations was heavily dependent on the establishment of open and efficient channels for information and data sharing. The integration of the scientific and clinical trial communities across both public and private sectors facilitated a methodical framework for the advancement of vaccines, encompassing their research, production, authorization, and dissemination. This facilitated the establishment of a cohesive objective with collective guidance, enabling the integration of scientific investigation within the framework of surveillance, manufacturing and scale-up, and public health implementation. The achievement of successful engagement with private industry, which typically exhibits hesitancy in investing in vaccines or biomedical interventions without proper management of confidentiality and financial risks, was facilitated by sustained communication and transparency. These efforts were complemented by the implementation of confidentiality protections and the mitigation of financial risks. It is imperative to consider the following factors in the development of an HIV vaccine, as governments strive to facilitate concrete solutions by implementing measures such as intellectual property and confidentiality protection, as well as providing funding to mitigate the risks associated with manufacturing investments throughout the vaccine development process.

Government-private partnerships (PPPs) are one type of hybrid partnership that can be used in the vaccine development process alongside private partnerships and governmental partnerships. PPPs are collaborative arrangements between for-profit and non-profit entities that aim to maximize social value and health outcomes. They’ve been crucial in getting us through the COVID-19 outbreak. Although a lot of work has already gone into figuring out what kinds of people work together, it’s also important to think about how they work together. In particular, the nature of the information exchanged between collaborators has consequences for both the specific nature of the collaboration and the evolution of relevant knowledge and technologies. To this end, we consider two distinct types of cooperation: (i) the exchange of information and technical know-how, and (ii) the transfer of physical resources, technological infrastructure, and intellectual property rights. In the first, one party benefits from the other’s knowledge and experience through an ongoing process of information and knowledge exchange. This helps both parties advance technologically while also expanding their future potential. The second model of innovation in partnership is based on the transfer of materials, technological infrastructure, and intellectual property from one partner to another in order to advance the innovation process. This is the traditional model for academic/industrial partnerships, in which universities and other research institutions provide knowledge and resources during the early phases of medication discovery while private companies help test and bring their medicines to market [35].

Additionally, the implementation of confidentiality protections and the mitigation of financial risks played a crucial role in this accomplishment.

The development of an HIV vaccine necessitates the careful consideration of various factors. As governments strive to find effective solutions, it is crucial to address certain aspects. These include the implementation of measures to protect intellectual property and maintain confidentiality, as well as providing funding to mitigate the risks associated with manufacturing investments made throughout the vaccine development process.

Addressing the intricate matter of vaccine equity is of paramount importance when considering the application of insights gained from the COVID-19 response to the realm of HIV vaccine research and development. Three crucial domains can be identified as significant in facilitating progress toward achieving fair distribution of vaccinations following their approval by regulatory authorities.

To facilitate the broader dissemination of vaccines, it is imperative to maintain ongoing governmental assistance in order to facilitate the expansion of manufacturing capabilities. The presence of fierce competition across the pharmaceutical and biotechnology sectors has posed challenges in effectively allocating COVID-19 vaccine developers to facilities that have sufficient capacity. In recent times, there have been ongoing endeavors to construct collaborative frameworks with the aim of creating such chances. An instance of cross-collaboration can be observed in the utilization of Sanofi facilities in France by Pfizer-BioNTech for vaccine production, as well as the establishment of an mRNA manufacturing hub in Africa [36, 37]. The implementation of regional manufacturing as a means to cater to the demands of neighboring nations has the potential to be economically viable and enhance the return on investment [38]. This leads to the enhancement of vaccine makers by offering information programs and professional training on technical advancements, conducting research on vaccine production, and promoting initiatives for technology transfer. The expansion and long-term sustainability of manufacturers in low- and middle-income countries are contingent upon the commitment of the government, policies that facilitate access to finance, and consistent support from independent National Regulatory Authorities [39]. The overarching progress in economic development has contributed to the expansion of both public and private access to capital. However, it is crucial to recognize the ongoing requirement for capital investment in order to effectively adhere to manufacturing regulations, such as the Current Good Manufacturing Practice, and embrace new production technology [40]. This poses a distinct challenge for manufacturers and warrants careful consideration by governments.

Furthermore, the establishment of efficient and effective vaccine supply chains is necessary in order to facilitate the expansion of production [41], especially in the underdeveloped countries, where the need for such care is exaggerated. Significantly, there has been a shift in focus within supply chain management from solely prioritizing risk management and efficiency to also encompassing resilience. The implementation of deliberate design and intervention methods will play a crucial role in sustaining immunization targets amidst ongoing interruptions in the supply chain [42]. In lieu of employing supply chain risk management strategies that prioritize supplier redundancies and flexible warehousing, the integration of resilience into the supply chain management process would entail the utilization of interchangeable and generic materials when feasible, the establishment of supplier contracts in diverse geopolitical regions, and the maintenance of an inventory buffer of critical raw materials. In addition to the previously mentioned regional manufacturing needs, it is important to consider the strategic approach of local resourcing and stockpiling of supplies as a means to mitigate supply chain shortages. By manufacturing, distributing, and storing supplies locally, the challenges associated with importing and exporting these resources can be minimized. One of the most significant consequences of the aforementioned techniques is the development and mobilization of indigenous personnel to effectively oversee a vaccine distribution network.

Furthermore, it is imperative for governments to consider the implementation of policies aimed at promoting equity. Relying just on market forces will not be sufficient to guarantee access and implementation in numerous lower-middle-income nations. In order to achieve economic growth and make strides toward eradicating poverty, it is imperative to ensure fair and equal access to vaccines among individuals residing in developing nations. This matter encompasses not alone a moral dimension necessitating altruistic behavior. Kremer and Rachel Glennerster investigated a funding method termed an advance market commitment (AMC) to increase enterprises’ incentives to sell vaccinations to low-income countries. Donors establish a subsidy fund through an AMC and pay firms a rebate for producing and selling the vaccine at a price close to their marginal cost, even in the “tail period” after the AMC subsidy money has run dry. Companies’ investments are safeguarded by the donors’ assurance that they will pay a subsidized price over cost. Market power distortions are reduced by the low price in the tail phase. To avoid having the program pay for items that fulfill the text of the contract terms (which are impossible to specify properly when set well in advance of production) but not user wants, the purchasing decision is ultimately decided by client countries and the product must pass the market test.

4. The issue of vaccine disparity poses a significant global health risk

When considering the application of insights gained from the COVID-19 pandemic to the domain of HIV, it is essential to acknowledge the longstanding presence of prosperous collaborations in the HIV vaccine field. These collaborations involve several stakeholders, including the business sector, academic institutions, and governmental bodies, all working toward common objectives. Nevertheless, it is possible to enhance our current collaborations by exploring methods to provide additional motivation to enterprises. This may be achieved by reducing the risks associated with product development through consistent funding and fostering open and clear communication from the first stages to the completion of the product development process. It is crucial to acknowledge that the market incentives for industry engagement in the development of an HIV vaccine will need to be considerably greater than those for the COVID-19 vaccine initiative. This is primarily due to several additional factors, including feasibility, costs (particularly for a regimen requiring multiple doses), regulatory obligations, manufacturing scale-up, and the distribution of an effective vaccine in high-incidence countries as opposed to industrialized nations.

The aforementioned obstacles will require the development of a robust business case in order to enhance the appeal of this venture from a commercial standpoint.

Flexibility is a crucial lesson that can be extrapolated and implemented in the context of HIV vaccine research in the future. The successful outcome heavily relies on the crucial aspect of interoperability among government-funded clinical networks, laboratories, and data-sharing systems. There is a need for alternative approaches to ascertain the possibilities not only in terms of infrastructure but also in terms of funding and collaboration methods that may be utilized to further the progress of HIV vaccine research and development. The COVID-19 response has been significantly influenced by the crucial early involvement of the Food and Drug Administration (FDA) in collaborating with product developers. The provision of explicit instructions by the FDA has additionally contributed to expediting the prompt and comprehensive evaluation of requests for Emergency Use Authorization (EUA). The capacity to engage in continuous dialogs throughout the course of the growth process is of utmost importance. Therefore, it is imperative to consider the development of updated and comprehensive guidance guidelines for HIV vaccine researchers in future endeavors. One of the primary factors to be considered as we transition into the post-pandemic era is the means by which we can maintain these labor-intensive and demanding dialogs for an extended duration.

The aforementioned procedures are crucial, since the COVID-19 pandemic has demonstrated the significant accomplishments that can be made in the field of research when there is collaboration and exchange of resources and creativity among governmental bodies, academic institutions, and biotechnology and pharmaceutical corporations. Ultimately, the successful implementation of a secure and efficient HIV vaccine necessitates the adoption of “all-of-government” strategy, characterized by transparency, consistent financial support, and the establishment of collaborative relationships between public and private entities. Additionally, the provision of clear regulatory directives is crucial in this endeavor. The most critical flexibility example in COVID-19 vaccine development was the fast-track approval by the health authorities to allow faster life-saving of millions of affected patients.

5. Promoting active involvement of affected and marginalized populations

The field of HIV clinical research has a notable tradition of actively involving communities, particularly those that are disadvantaged, both within the country and across borders, throughout the initial stages of the study process. Indeed, the field of HIV research has significantly advanced the notion of community involvement and inclusivity, to the extent that it has become comprehensible, instructive, and widely accepted [43]. Furthermore, the area of HIV research acknowledges the significance of rapidly and effectively disseminating the conclusions of clinical trials, regardless of whether they are positive or negative, in a manner that is clear, accurate, and considerate. Nevertheless, valuable insights can still be derived from the COVID-19 pandemic. During the initial and middle phases of 2020, there was a rapid dissemination of the SARS-CoV-2 virus across the United States, with a notable impact on racial and ethnic minority groups who were already facing health disparities [44]. Ensuring the participation of these populations in COVID-19 clinical trials was a primary objective for the Government, resulting in numerous outreach initiatives [45]. As an illustration, the National Institutes of Health (NIH) established the Community Engagement Alliance team with the purpose of addressing the specific requirements of the communities that have been most affected by SAR-CoV-2.

Simultaneously, the CoVPN enhanced its community engagement efforts by creating many Expert Panels consisting of medical, scientific, and social science professionals representing diverse racial/ethnic backgrounds, as well as older adults and veteran populations. Furthermore, the COVID-19 Prevention Network (CoVPN) strengthened its efforts to engage with many communities by implementing the Faith Initiative, which involved the establishment of Faith-Leadership organizations. The CoVPN Faith Initiative is a program of national scope in the United States that is grounded in faith-based principles. Its primary objective is to foster trust and facilitate meaningful involvement within specific communities. This initiative achieves its goals by disseminating accurate and up-to-date information regarding COVID-19 and CoVPN clinical trials. It accomplishes this through the collaborative efforts of seven designated “faith ambassadors” and over 30 clergy-consultants who represent the Black, Latinx, and American Indian/Alaska Native communities. The aforementioned faith leaders have been entrusted with the responsibility of executing a COVID-19 and CoVPN education initiative that is centered around faith and aims to facilitate the active involvement of those belonging to significant groups. A key aspect of the community outreach efforts revolved around the consistent and timely communication throughout the study process, as well as the effective management of communications at the local level.

Significantly, these outreach organizations endeavored to acknowledge and uphold the agency and autonomy of communities as collaborative partners in the process, leading to a fairer and mutually beneficial bidirectional relationship.

The medical research enterprise is subject to a prevailing sense of mistrust, primarily stemming from a legacy of unethical research practices, especially those conducted by the United States government [46]. This sentiment persists within some populations. Furthermore, it is important to acknowledge that structural and systemic racism is a pervasive phenomenon that individuals encounter on a daily basis within many communities. This form of racism has the potential to significantly affect individuals’ ability to obtain essential services and medical care [47]. Ensuring transparency and fostering active communication were crucial in establishing trust within these communities, thereby instilling confidence in the system and encouraging participants to actively participate as partners in clinical studies for COVID-19. As a component of this collaboration, the government also ensured that communities most affected by the COVID-19 pandemic were granted timely access to vaccines as soon as they were made available through Emergency Use Authorization (EUA) or licensure.

The area of HIV vaccine research can further advance by prioritizing ongoing community interaction and actively addressing misunderstanding and disinformation. One notable consequence of the COVID-19 epidemic has been the considerable improvement in scientific literacy among the general population [48, 49]. The area of HIV research should capitalize on this current enthusiasm by implementing public education initiatives.

It is of utmost importance for researchers to acknowledge and address the worries of persons regarding mistrust and reluctance. Additionally, researchers should strive to comprehend the goals of communities in order to effectively cater to their requirements. In numerous groups, the prevalence of prejudice and neglect in the past and/or present can account for the skepticism surrounding research trials and the reluctance to engage in vaccine participation [50]. Furthermore, the historical occurrence of medical injustices inflicted upon many populations has significantly contributed to the cultivation of mistrust and skepticism. This suspicion extends even to ethically conducted medical and public health interventions that have been scientifically validated as both safe and efficacious.

It is imperative for researchers to consistently enhance existing connections founded on trust, or establish new ones in cases where trust is lacking. Several strategies can be employed to enhance this reciprocal association, including the facilitation of grassroots communication initiatives at the regional level and the augmentation of community advisory boards to encompass a greater representation of community members and advocates, such as leaders affiliated with faith-based organizations.

The COVID-19 vaccination trials were able to effectively utilize online platforms to access populations that were most affected by the pandemic, hence facilitating the mobilization of resources. These platforms were essential in using real-world surveillance data. This was demonstrated through the implementation of mobile units and satellite sites that were associated with the clinical research sites and strategically situated in communities that were significantly affected.

These measures effectively improved the visibility and accessibility of the research efforts. The mobilization resources encountered many problems, such as scalability, operability, and deployment. Nevertheless, there are valuable insights that may be gained in order to enhance these processes, such as optimizing the procedures for granting approvals and integrating satellite locations, both within the country and across borders.

A crucial aspect of engaging with affected populations in the United States is the integration of up-to-date data with epidemiological modeling in order to assess the spatial, temporal, and demographic vulnerabilities. This was particularly crucial during the onset of the COVID-19 pandemic for the purpose of finding clinical sites that had the capacity to enroll the communities that were most affected within the epicenters of the virus. This methodology facilitated expedited accumulation of endpoint data and guaranteed the inclusion of a wide range of demographic groups in the study population.

The field of HIV vaccine research is positioned to make significant progress in proven epidemiological methods, such as incorporating artificial intelligence and machine learning technology to improve epidemic modeling and assess the effectiveness of interventions.

The utilization of COVID-19 registries has enhanced the utility of epidemiological data by facilitating the selection of participants based on geographical area and specific risk factors, thereby enabling researchers to focus on individuals who are of particular interest. The COVID-19 register, initiated by the United States Government in collaboration with business partners, proved to be highly effective as it garnered participation from a substantial number of persons, exceeding 700,000 entries. The register was utilized by numerous clinical locations to gain access to priority groups with the aim of expediting the process of enrollment.

The approach being considered by the HIV vaccine field involves the establishment of the Red-Ribbon Registry. This registry, accessible at https://www.helpendhiv.org/redribbon-registry/, would serve as a screening tool to identify individuals who may be suitable candidates for participation in HIV clinical trials conducted by HIV clinical trial networks funded by the National Institute of Allergy and Infectious Diseases (NIAID). The promotion of such registries has the potential to significantly expedite the recruitment of key populations for future clinical trials.

There are valuable insights to be gained from the modifications implemented in clinical trials to effectively engage and serve affected populations. One notable characteristic of the COVID-19 studies was the inclusion of an extra virtual element in these investigations. This addition was prompted by various considerations, including the urgency for rapid results and the requirement to isolate patients exhibiting signs of COVID-19. Furthermore, apart from the provision of flexible appointment time slots and the availability of home visits, there were also instances where remote visits were feasible, particularly in cases where blood work was not required. Research studies have successfully employed electronic diaries to enable and sustain remote communication for virtual data gathering. Nevertheless, it was imperative for the ‘low-touch’ data gathering platforms to be user-friendly for the end-users. We are currently engaged in an ongoing process of learning and enhancing the technologies that were employed during the COVID-19 pandemic. The inclusion of senior persons, who are more susceptible to experiencing severe cases of COVID-19, in the studies was of significant importance. Moreover, it is crucial to consider the provision of additional computer literacy training to facilitate electronic reporting. Given that the clinical trials were conducted, at least in part, within underserved regions characterized by gaps in smartphone and internet accessibility, ensuring that all study participants had access to these devices and the internet was of utmost importance.

The utilization of virtual communication and data collecting is a significant breakthrough with the capacity to enhance recruitment efforts and improve participant retention rates.

6. Exchanging the emerging evidence expedites the advancement of knowledge and development

Undoubtedly, significant advancements in scientific research have been achieved throughout the preceding two-year period. The rapid pace of progress in addressing the COVID-19 pandemic can be attributed to several factors. Adequate funding and the ability to shift resources from HIV research to COVID-19 played a role in expediting this progress. Additionally, an unprecedented research approach characterized by open access, extensive collaboration, and transparency significantly contributed to the swift dissemination of information among a diverse set of stakeholders, including both public and private entities. Several scientific publications expedited the dissemination of COVID-19 research, facilitating the timely availability of groundbreaking findings to the public. This strategy has the potential to significantly expedite research on HIV as well. In order to enhance the productivity of data sharing, it is imperative for scientists to enhance and optimize strategies for the integration of data from diverse sources.

This is because data obtained from various studies are frequently characterized by a lack of standardization and are dispersed throughout numerous segregated repositories. One potential approach is adhering to the guiding principles of FAIR, which encompass findability, accessibility, interoperability, and reusability.

An additional approach that is presently being pursued involves the establishment of centralized platforms for the purpose of exchanging data that have been amalgamated from various sources.

7. Potential areas for enhancement

It is imperative to recognize the limits inherent in the reaction to the COVID-19 epidemic, such as those exhibited by the United States Government. The swift and effective progress in the development and subsequent authorization of several vaccines has hindered the opportunity for comprehensive assessment of the long-term comparative effectiveness of various vaccines and combinations. This has also limited the availability of large-scale randomized placebo-controlled trials for new vaccines, as well as studies conducted in populations with no prior exposure to these vaccines.

Furthermore, the limited timeframe available for optimizing vaccine doses and schedules has resulted in ongoing issues pertaining to the determination of optimal vaccine dosing intervals and strategies for maximizing vaccine durability. Over the course of time, the significance of vaccination effectiveness in populations without prior exposure has diminished, along with the value of vaccine efficacy against previously prevalent viruses in this ever-changing pandemic situation. The inclusion of these vulnerable people, such as individuals who have had organ transplantation, cancer patients undergoing chemotherapy, pregnant ladies, and young children, in a timely manner could lead to the development of more educated vaccine strategies that would benefit a larger population. Gaining insights from these constraints will enhance the efficacy of vaccine development approaches for HIV and forthcoming global health crises. Further research is warranted to incorporate a greater representation of particular populations, including individuals who are living with HIV/AIDS.

8. Conclusion

The scientific community demonstrated exceptional swiftness and precision in addressing the obstacles posed by the COVID-19 pandemic through the creation of secure and efficacious vaccinations. The present moment is an opportune time to leverage the combined momentum generated by the COVID-19 pandemic in order to address the challenges posed by HIV. Across the various approaches delineated in this discourse, several overarching themes become apparent: the utmost importance of flexibility in effectively addressing a dynamic pandemic; the enhancement of equity in vaccine, therapeutic, and service accessibility for communities disproportionately affected by a pandemic through inclusion (although international access remains an ongoing obstacle), which also fosters diverse perspectives and enhances decision-making; the indispensable role of transparency in expediting scientific progress and fostering trust; and the ongoing necessity of sustained investment in fundamental research to advance the quest for an effective HIV vaccine. By assimilating these significant lessons, the scientific community can leverage the impetus gained from the COVID-19 experience to invigorate the development of an HIV vaccine.