Year: 2024
Type: article
Abstract: Vaccination is one of the most effective public health tools ever developed, having saved an estimated 154 million lives in the past 50 years alone [1]. Vaccine technologies have evolved from the crude practice of variolation to the cutting-edge immunogen design, vaccine platforms, adjuvant science, and preclinical and clinical testing paradigms that exist today. During the coronavirus disease 2019 (COVID-19) pandemic, the development and implementation of these approaches were accelerated, ushering in a new era of vaccine science where structure-based immunogen design, plug-and-play vaccine platforms, and historic vaccine development partnerships took center stage. COVID-19 also offered an unprecedented opportunity to understand protective immune responses to infection and from vaccination, the role of imprinting in the immune response to vaccines, and correlates of protection for different vaccine platforms utilizing the same immunogen. The pandemic revealed that, with enough funding and political will, vaccine development and approval can occur in a fraction of the time that is usually required. However, COVID-19 also laid bare inequities in global vaccine access. These inequities have been evident for decades with distribution of other vaccines. For example, elimination of cervical cancer through human papillomavirus (HPV) vaccination is now within reach for high-income countries, while women who suffer the most from cervical cancer in low-income settings had virtually no country-level access to HPV vaccines until recently. During the COVID-19 pandemic, inequities in vaccine distribution were amplified due to the added expense of novel platforms and the unprecedented intensity of global demand. While we have work to do to achieve equity in vaccine access, the World Health Organization (WHO), global donors, and philanthropic organizations have made amazing strides in the delivery of routine childhood vaccines in low- and middle-income countries through the Expanded Programme on Immunization (EPI). A recent analysis suggests this program is the single greatest contributor to improved infant survival over the past 50 years [1]. The EPI aims to make further progress in providing vaccines for both children (HPV, malaria, meningitis) and adults (COVID-19, respiratory syncytial virus) [1]. The need for vaccine equity during a pandemic response has been recognized as urgent and is one of the critical elements under negotiation as part of the Pandemic Accord [2]. Despite dramatic advances in vaccine science, new approvals for vaccines for both children and adults, and improved global vaccine coverage, several infectious diseases remain top causes of death and disability. Human immunodeficiency virus (HIV), tuberculosis, and malaria [3], in particular, have proven themselves to be challenging vaccination targets for both scientific (eg, complex infection cycles, high degree of pathogen variability) and nonscientific (eg, need for large and lengthy clinical trials and limited potential market in high-income countries) reasons. Nevertheless, there is hope that recent vaccine approvals (malaria), the launch of long-awaited pivotal trials (tuberculosis), and new technological advances may identify solutions for these challenging killer pathogens. Malaria is the leading infectious cause of disability-adjusted life years (DALYs) in children under 5 years of age [4] and disproportionately impacts sub-Saharan Africa. Malaria parasites pose significant obstacles to vaccine development, including complex lifecycles, diverse strains, polymorphic invasion molecules, and redundant biological pathways. Despite these challenges, the WHO has recently recommended 2 related vaccines for the prevention of Plasmodium falciparum malaria in children living in endemic areas: RTS,S/AS01 and R21-Matrix-M. Both vaccines target preerythrocyte (sporozoite/liver) stage malaria, require multiple doses, and provide limited durability of immune response; therefore, new vaccines are needed to address different life stages, improve efficacy and durability of immune response, and protect against non-falciparum species. In addition to the approved malaria vaccines, there are 15 preerythrocyte vaccine candidates in active phase 1 or 2 clinical development, including 1 for Plasmodium vivax [5]. Vaccines targeting the merozoite (blood) stage of the malaria parasite are also desirable, as this is the stage that causes disease; however, challenges include redundant invasion pathways, limited exposure of the merozoites to antibodies during infection, and large pathogen burden in the blood [6]. There are 15 blood-stage vaccine candidates in active phase 1 or 2 clinical development, including 2 for P. vivax [5]. Finally, there is a need for transmission-blocking vaccines (TBVs) targeting the mosquito/sexual stage of the parasite to interrupt parasite transmission from the infected person to the vector. As this approach confers benefit at the population level but may not prevent illness in the vaccinated person, TBV candidates will require an immaculate safety profile, the ability to elicit high and durable antibody levels, and widespread adoption to achieve success [6]. There are 9 TBV candidates in phase 1 or phase 2 clinical trials, including 2 for P. vivax [5]. Another promising tool for malaria prevention is monoclonal antibodies used for passive immunization. Results of a recent phase 2 trial of the monoclonal antibody L9LS in adults and children in Mali demonstrated high levels of protection from malaria infection (70%) and clinical disease (77%) in the high-dose group 6 months postinjection. This approach may prove favorable in certain populations; additional trials are in progress [7]. Tuberculosis has afflicted humanity for millennia and remains the leading infectious disease-related cause of DALYs globally [3]. The BCG vaccine, more than a century old, offers some protection against tuberculosis and death in children, but does little to prevent pulmonary tuberculosis in adolescents and adults [8]. While the field of tuberculosis vaccines moves slowly relative to other disease areas due to limited resources and large and lengthy pivotal trials, the vaccine pipeline is currently more robust than it has ever been [9]. The M72 AS01E vaccine demonstrated 49.7% efficacy in preventing disease in a phase 2b trial in tuberculosis-infected adults and there is much excitement surrounding the March 2024 launch of the phase 3 trial of this candidate [10]. Correlates of protection analysis is underway for both the M72 phase 2 and another phase 2 trial in adolescents revaccinated with BCG to prevent infection. A validated correlate of protection could serve as a biomarker in future trials, thus facilitating smaller and faster answers from tuberculosis vaccine trials [11]. In addition to the M72 vaccine, live attenuated vaccine candidates VPM1002 and MTBVAC, designed to be safer and more effective alternatives to BCG, have also entered phase 3 trials. There are 9 additional protein, viral vector, and mRNA-based candidates in phase 1 and 2a trials, bringing more robust diversity to the pipeline [9]. While the availability of antiretroviral therapy (ART) for HIV has revolutionized the prognosis of those living with HIV, 1.3 million new people are infected each year [12] and HIV remains the third leading cause of infectious disease-associated DALYs [4]. A vaccine is still a critical goal. Decades of investment in HIV vaccines have produced many candidates but only disappointing results in efficacy trials. HIV presents challenges for vaccine design, including complex mechanisms of immune evasion and vast sequence and antigen diversity [13]. The recent failures of candidates stimulating nonneutralizing antibodies or T-cell responses, combined with encouraging proof-of-concept trials of broadly neutralizing antibodies (bnAbs) administered prophylactically [14] have refocused attention on vaccine strategies to produce bnAbs [15]. This is not straightforward: bnAbs are only very rarely produced by HIV-infected individuals and vaccination approaches that can effectively induce them are not yet clear. The HIV vaccine field is now focusing on iterative design and testing of vaccination strategies that can effectively induce protective bnAb responses, while also engaging other arms of the immune system [13]. bnAbs themselves may pose an alternative prevention strategy for HIV through passive immunization, and several large clinical trials are ongoing. It is unclear whether bnAbs will be able to provide sufficiently broad coverage of ever-evolving strains, whether the cost of goods and implementation challenges could be overcome, and whether this approach would add value to the existing armamentarium of long-acting ART. Nevertheless, bnAb trials are providing important information about the level and characteristics of antibodies that provide protection [13]. Finally, it is important to note that the investments made in HIV vaccines have borne other fruits, including the structure-guided vaccine design and global clinical trials networks that were critical to the development and testing of COVID-19 vaccines [16]. On the heels of the COVID-19 pandemic, there is a global outcry not just for access, but also for development and local production of vaccines in regions that have not had this capacity to date, such as sub-Saharan Africa [17]. Developing the capacity for every region to produce their own vaccines may promote equity in access for both endemic and outbreak-related diseases. It would also provide critical surge capacity during future pandemics. Obstacles include sustainable financing, intellectual property concerns, and consistent maintenance of the facilities and technical workforce needed to produce vaccines, which may require political will and resources comparable to those applied to rapid development of COVID-19 vaccines. Globally, there are promising developments in Africa (African Union/Africa Centers for Disease Control and Prevention's Vaccine Manufacturing Framework for Action [18], WHO's mRNA vaccine technology transfer hub in South Africa), South America (Instituto Butantan), and Asia (Serum Institute of India, International Vaccine Institute), which may provide roadmaps and infrastructure to move toward the global health goal of distributed vaccine manufacturing. Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases.
Authors: Jane M Knisely, Emily Erbelding
Language: English
Subfield: Health
Field: Social Sciences
Domain: Social Sciences
Open Access status: green
OpenAlex ID: W4403516801