A peer says the government is "in deep shit,” and it couldn't be more real

Study after study in The BMJ and other major journals has indicated the effectiveness of this vaccine technology (doi:10.1136/bmj.o2865 doi:10.1136/bmj-2022-073070 doi:10.1136/bmj-2022-072065).567 Now, a new study in The BMJ shows that maternal mRNA covid-19 vaccination during pregnancy protects infants against SARS-CoV-2 infection and hospital admission (doi:10.1136/bmj-2022-074035).8 It is perfectly reasonable to hold an evidence informed view that mRNA vaccines are effective against SARS-CoV-2 and should be widely administered while demanding full disclosure of the safety data (doi:10.1136/bmj.o102).9 As this study of vaccination in pregnancy highlights, there are also other nuances that must be considered before research evidence becomes policy, such as timing of treatment (doi:10.1136/bmj.p241).10 Vaccine manufacturers' next goal is to develop mRNA vaccines to prevent cancer, one of the original ambitions for this breakthrough science (doi:10.1136/bmj.o3041).1 Research is already advanced, although a reasoned debate on the wider application of mRNA vaccines seems unlikely. The political or commercial control of public interest data is an undesirable endpoint worthy of Warneresque levels of plain speaking condemnation. 1 Baraniuk C. When will the world get cancer vaccines? BMJ 2023;380: o3041. 10.1136/bmj.o3041 36609365 2 McEvoy J. Microchips, magnets and shedding: here are 5 (debunked) covid vaccine conspiracy theories spreading online. Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study.

Circular RNA cancer vaccines drive immunity in hard-to-treat malignancies.

Rationale: Messenger RNA (mRNA) vaccine outperforms other kinds of cancer immunotherapy due to its high response rates, easy preparation, and wide applicability, which is considered as one of the most promising forms of next-generation cancer therapies. However, the inherent instability and insufficient protein expression duration of mRNA limit the efficacy and widespread application of the vaccine. Methods: Here, we first tested the possibility of a novel circular RNA (circRNA) platform for protein expression and compare its duration with linear RNA. Then, we developed a lipid nanoparticle (LNP) system for circRNA delivery in vitro and in vivo. Next, the innate and adaptive immune response of circRNA-LNP complex was evaluated in vivo. The anti-tumor efficacy of circRNA-LNP was further confirmed in three tumor models. Finally, the possibility of combination therapy with circRNA-LNP and adoptive cell transfer therapy was further investigated in a late-stage tumor model. Results: We successfully increased the stability of the RNA vaccine by circularizing the linear RNA molecules to form highly stable circRNA molecules which exhibited durable protein expression ability. By encapsulating the antigen-coding circRNA in LNP enabling in vivo expression, we established a novel circRNA vaccine platform, which was capable of triggering robust innate and adaptive immune activation and showed superior anti-tumor efficacy in multiple mouse tumor models. Conclusions: Overall, our circRNA vaccine platform provides a novel prospect for the development of cancer RNA vaccines in a wide range of hard-to-treat malignancies.

Current Developments and Challenges of mRNA Vaccines.

mRNA vaccines have brought about a great revolution in the vaccine fields owing to their simplicity and adaptability in antigen design, potential to induce both humoral and cell-mediated immune responses and demonstrated high efficacy, and rapid and low-cost production by using the same manufacturing platform for different mRNA vaccines. Multiple mRNA vaccines have been investigated for both infectious diseases and cancers, showing significant superiority to other types of vaccines. Although great success of mRNA vaccines has been achieved in the control of the coronavirus disease 2019 pandemic, there are still multiple challenges for the future development of mRNA vaccines. In this review, the most recent developments of mRNA vaccines against both infectious diseases and cancers are summarized for an overview of this field. Moreover, the challenges are also discussed on the basis of these developments.

Vaccination against Cancer or Infectious Agents during Checkpoint Inhibitor Therapy.

The use of immune checkpoint inhibitors (ICI) has substantially increased the overall survival of cancer patients and has revolutionized the therapeutic situation in oncology. However, not all patients and cancer types respond to ICI, or become resistant over time. Combining ICIs with therapeutic cancer vaccines is a promising option as vaccination may help to overcome resistance to immunotherapies while immunotherapies may increase immune responses to the particular cancer vaccine by reinvigorating exhausted T cells. Thus, it would be possible to reprogram a response with appropriate vaccines, using a particular cancer antigen and a corresponding ICI. Target populations include currently untreatable cancer patients or those who receive treatment regimens with high risk of serious side effects. In addition, with the increased use of ICI in clinical practice, questions arise regarding safety and efficacy of administration of conventional vaccines, such as influenza or COVID-19 vaccines, during active ICI treatment. This review discusses the main principles of prophylactic and therapeutic cancer vaccines, the potential impact on combining therapeutic cancer vaccines with ICI, and briefly summarizes the current knowledge of safety and effectiveness of influenza and COVID-19 vaccines in ICI-treated patients.

Delivery of STING agonists for adjuvanting subunit vaccines.

Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy of vaccines. Recently discovered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has attracted much attention as it is a key mediator for modulating immune responses. Vaccines adjuvanted with STING agonists are found to mediate a robust immune defense against infections and cancer. In this review, we first discuss the mechanisms of STING agonists in the context of vaccination. Next, we present recent progress in novel STING agonist discovery and the delivery strategies. We next highlight recent work in optimizing the efficacy while minimizing toxicity of STING agonist-assisted subunit vaccines for protection against infectious diseases or treatment of cancer. Finally, we share our perspectives of current issues and future directions in further developing STING agonists for adjuvanting subunit vaccines.

Emerging Concepts and Technologies in Vaccine Development.

Despite the success of vaccination to greatly mitigate or eliminate threat of diseases caused by pathogens, there are still known diseases and emerging pathogens for which the development of successful vaccines against them is inherently difficult. In addition, vaccine development for people with compromised immunity and other pre-existing medical conditions has remained a major challenge. Besides the traditional inactivated or live attenuated, virus-vectored and subunit vaccines, emerging non-viral vaccine technologies, such as viral-like particle and nanoparticle vaccines, DNA/RNA vaccines, and rational vaccine design, offer innovative approaches to address existing challenges of vaccine development. They have also significantly advanced our understanding of vaccine immunology and can guide future vaccine development for many diseases, including rapidly emerging infectious diseases, such as COVID-19, and diseases that have not traditionally been addressed by vaccination, such as cancers and substance abuse. This review provides an integrative discussion of new non-viral vaccine development technologies and their use to address the most fundamental and ongoing challenges of vaccine development.