Achieving end-to-end success in the clinic: Pfizer's learnings on R&D productivity.

Over the past decade, Pfizer has focused efforts to improve its research and development (R&D) productivity. By the end of 2020, Pfizer had achieved an industry-leading clinical success rate of 21%, a tenfold increase from 2% in 2010 and well above the industry benchmark of ∼11%. The company had also maintained the quality of innovation, because 75% of its approvals between 2016 and 2020 had at least one expedited regulatory designation (e.g., Breakthrough Therapy). Pfizer's Signs of Clinical Activity (SOCA) paradigm enabled better decision-making and, along with other drivers (biology and modality), contributed to this productivity improvement. These laid a strong foundation for the rapid and effective development of the Coronavirus 2019 (COVID-19) vaccine with BioNTech, as well as the antiviral candidate Paxlovid™, under the company's 'lightspeed' paradigm.

Innovation in breakthrough drugs and vaccines: Development risk, patient impact, and value.

Innovation has a crucial role in developing breakthrough drugs and vaccines that can change patients' lives. To better understand this role, we evaluated recent outcomes for assets developed using different types of innovation. Although all approaches have delivered breakthroughs, assets that modulate established biological targets with innovative scientific or technological designs provide a unique combination of reduced development risk, high patient impact, and high commercial value. This type of asset currently represents a relatively small proportion of approved drugs and vaccines, but we anticipate that an increasing body of scientific knowledge and ongoing technological advancements could offer opportunities to grow this category in the future.

Reviving an R&D pipeline: a step change in the Phase II success rate.

The pharmaceutical industry has faced declining research and development (R&D) productivity for decades. During the early 2010s, Pfizer saw its R&D productivity drop even more sharply than did its industry peers. As impactful medicines the company had developed and brought to patients in previous years lost exclusivity, Pfizer faced a steep patent cliff with a cumulative revenue impact of >US$28 billion through 2018. Since 2010, the company has embarked on a focused turnaround effort to improve R&D productivity. Although some efforts will need more time to prove themselves, there are early signs of a turnaround now, particularly in terms of Phase II success rates. Here, we share some learnings from a decade of experience as one of the largest R&D organizations in the industry.

HIV envelope suppresses CD4+ T cell activation independent of T regulatory cells.

We previously demonstrated that HIV envelope glycoprotein (Env), delivered in the form of a vaccine and expressed by dendritic cells or 293T cells, could suppress Ag-stimulated CD4(+) T cell proliferation. The mechanism remains to be identified but is dependent on CD4 and independent of coreceptor binding. Recently, CD4(+) regulatory T (Treg) cells were found to inhibit protective anti-HIV CD4(+) and CD8(+) T cell responses. However, the role of Tregs in HIV remains highly controversial. HIV Env is a potent immune inhibitory molecule that interacts with host CD4(+) cells, including Treg cells. Using an in vitro model, we investigated whether Treg cells are involved in Env-induced suppression of CD4(+) T cell proliferation, and whether Env directly affects the functional activity of Treg cells. Our data shows that exposure of human CD4(+) T cells to Env neither induced a higher frequency nor a more activated phenotype of Treg cells. Depletion of CD25(+) Treg cells from PBMC did not overcome the Env-induced suppression of CD4(+) T cell proliferation, demonstrating that CD25(+)FoxP3(+) Treg cells are not involved in Env-induced suppression of CD4(+) T cell proliferation. In addition, we extend our observation that similar to Env expressed on cells, Env present on virions also suppresses CD4(+) T cell proliferation.

Vaccine-delivered HIV envelope inhibits CD4(+) T-cell activation, a mechanism for poor HIV vaccine responses.

The human immunodeficiency virus (HIV) causes impairment of the immune system in part by targeting CD4(+) T cells for infection and dysfunction. HIV envelope (Env) present on free virions and infected cells causes dysfunction of uninfected bystander CD4(+) T cells via interaction with both CD4 and coreceptors. Env is commonly used as part of a cocktail of HIV antigens in current vaccines. In DNA and viral vector vaccine approaches, antigen-presenting cells (APCs) and non-APCs in the vicinity of the vaccine delivery site and draining lymph node express vaccine-derived antigens. The studies here demonstrate that cell-surface expression of Env on APCs and non-APCs as part of the vaccine action causes an inhibition of antigen-induced CD4(+) T-cell activation and proliferation mediated by CD4 binding and suggests a potential mechanism for reduced activity of Env-containing HIV vaccines. Similar studies using a functional Env lacking CD4 binding circumvented suppression, suggesting an alternative and potentially superior approach to HIV vaccine design.