February 3, 2021 - Recent progress made with messenger RNA vaccines has led to amplified protein translation, stronger modulation of immunogenicity, and improved delivery, which has all contributed to an evolution in the application of these products in the field of cancer.
Recent progress made with messenger RNA (mRNA) vaccines has led to amplified protein translation, stronger modulation of immunogenicity, and improved delivery, which has all contributed to an evolution in the application of these products in the field of cancer.
These advances also set the stage for the fastest development and approval of a vaccine against a novel pathogen in medical history, according to Ugur Sahin, MD, of Johannes Gutenberg-University Mainz, BioNTech SE, in Mainz, Germany. Sahin was involved in the research that went into BNT162b2, the first vaccine to receive Emergency Use Authorization by the FDA for the prevention of coronavirus disease 2019 (COVID-19) in individuals aged 16 years and older.
In a Keynote presentation delivered during the 2021 AACR Virtual Meeting on COVID-19 and Cancer, Sahin shed light on the impact of structural mRNA modifications, how mRNA has been optimized for expression and delivery into dendritic cells, the different mRNA vaccines that have been developed and how they compare with one another, and how these vaccines have emerged as an effective weapon in the fight against COVID-19.1
mRNA vaccines are produced by enzymatic in vitro transcription from a DNA template. The mRNA is purified and formulated into a nanoparticulate. The formulation ensures that the mRNA is protected from degradation by extracellular RNAses and it allows for stronger delivery of the mRNA-encoded genetic information to the cells within the patient.
“Certain structural elements control the activity of the mRNA. Over the past decades, several structure, sequence-based, or biochemical modifications have been described,” said Sahin. “These impact the expression of the mRNA, the strength of the translation, and the half-life. A combination of modifications can be used to prolong the translation of the mRNA, to increase the translation, or to [achieve] a combined effect. With these combinations, the potency of the mRNA can be improved.”
Sahin added that 2 decades ago, established RNA vaccine vectors had relatively poor potency that did not allow for strong immune responses. As such, a key goal of the research that has been done in this area was focused on improving upon that potency.
To this end, several studies were conducted to further examine structural mRNA components and identify how they contributed to antigen expression and mRNA stability, explained Sahin. With this understanding, investigators were able to determine several ways in which they could increase intracellular stability of the mRNA and to improve the translation of encoded proteins to human dendritic cells, which are key regulators of adaptive immunity.2-4
Other efforts were made to allow for selective mRNA targeting to lymphoid dendritic cells. “We accomplished that with a lipoplex formulation that can be administered intravenously, thereby reaching lymphoid dendritic cells in the spleen and lymph nodes,” noted Sahin; this allows for optimal antigen presentation and immune response activation.5
In the past 10 years, mRNA vaccines have been developed for use within the field of cancer, for the prevention of infectious diseases, and most recently, for antigen-specific tolerance induction in autoimmune diseases. Each application is described by the profile of the target antigens, the type and chemistry of the mRNA, and the delivery method by which immune effectors are induced via immunization, explained Sahin.
“A key characteristic of the messenger RNA technology is the versatility and the speed with which such vaccines can be developed,” said Sahin. “This versatility allows for the tailoring of the individual vaccines and the development of these vaccines in an extremely fast fashion.”
One example of this was the development of personalized neoantigen vaccines, added Sahin; these vaccines are tailored to the neoantigen profile of each individual patient, they are produced on demand, and are developed within a couple of weeks. In early-phase trials, these vaccines have been shown to elicit neoantigen-specific immune responses that were linked with clinical benefit and the reduction of cumulative metastatic recurrences in patients with melanoma.6-7
Another class of mRNA vaccine have been developed to target nonmutated tumor-associated antigens (TTA). “Such targets are attractive since they are shared and expressed in multiple tumor indications,” said Sahin. “However, immune responses in [these earlier] trials were weak.” To improve upon this, they introduced a new means of delivery, to better translate antigens to lymphoid dendritic cells; this resulted in strong CD8 and CD4 T-cell responses.
“Such strong T-cell responses are associated with objective responses in patients with advanced melanoma, either with the vaccine alone or the vaccine in combination with anti–PD-1 treatment,” noted Sahin.
By using the same delivery platform, investigators were able to deliver targeted antigens recognized by CAR T cells to stimulate and expand those T cells in vivo. With the 2-part CARVac (CAR-T cell Amplifying RNA Vaccine) strategy, investigators introduced claudin 6 as a new CAR T-cell target and designed a nanoparticulate RNA vaccine that encoded a chimeric receptor directed toward the target.8 By promoting the expression of claudin-6 on the surface of dendritic cells, the vaccine is able to stimulate and augment the efficacy of the CAR T cells.
COVID-19, a disease caused by a new coronavirus referred to as SARS-CoV-2, was first recognized by the World Health Organization (WHO) on December 31, 2019, after a cluster of viral pneumonia cases had been reported in Wuhan, People’s Republic of China.9 The virus has rapidly spread across the globe since then.
As of February 3, 2021, the Centers for Disease Control and Prevention report a total of 26,277,125 total cases in the United States, with at least 445,264 deaths reported.10 In the latest weekly epidemiological update issued by the WHO on February 2, 2021, 3.7 million cases were reported within the past week alone. Compared with the previous week, however, the number of new cases declined by 13%, according to the report.11
In response to the pandemic, investigators worldwide got to work to quickly engineer, manufacture, and test several mRNA vaccine candidates. Of the different products that Sahin worked with, the BNT162b2 emerged as the optimal candidate. To test the candidates, investigators examined dose-dependent tolerability and immunogenicity profiles, which included the evaluation of neutralizing antibody responses and T-cell responses, said Sahin.
“BNT162b2 induces strong dose-dependent antibody responses with significant induction of antibodies, even at the lowest dose of 1 μg,” said Sahin. “The 30-μg dose turned out to be the optimal dose, as it enabled strong neutralizing and lasting antibody responses in younger adults, as well as in those older than 65 years. The [vaccine] also induces strong expansion of CD4 and CD8 T-cell responses with the detection of responses in all vaccinated [patients].”
Data from a phase 3 pivotal trial (NCT04368728) showed that among 43,448 patients, the vaccine showcased a 95% efficacy with regard to COVID-19 infection prevention in those who were not previously infected 7 days or longer following the second vaccine dose.12 The efficacy of BNT162b2 was noted in the overall population of patients analyzed, as well as across several subsets like age, gender, race, ethnicity, baseline body mass index, or other comorbidities.
According to Sahin, 1 key remaining question is whether vaccination with BNT162b2 will be able to prevent against infection with other emerging virus variants. The variant B.1.1.7 has been identified in the United Kingdom that might be linked with an increased risk of death versus other variant viruses.13 Additionally, in South Africa, the B.1.351 variant has emerged, while in Brazil, the P.1 variant has been detected. According to the CDC, these variants appear to spread more easily and more rapidly than others, which could lead to more cases of COVID-19.
“What is currently not known is how SARS-CoV-2–specific CD4 and CD8 T cells contribute to infection and disease control of such variants,” admitted Sahin “This question is important since T cell epitopes are not expected to be significantly impacted by clonal evolution and immune escape.”