May 15, 2020
While there are many open questions about managing the current pandemic, there seems to be universal agreement that the best case solution is the creation of an effective vaccine to SARS-CoV-2, the coronavirus that causes COVID-19.
The following are some of our notes about vaccine development.
1/ A good overview of the global effort to develop a vaccine against SARS-CoV-2 written by the Coalition for Epidemic Preparedness Innovations (CEPI) can be found here. The CEPI/World Health Organization are maintaining and updating a database of vaccine development efforts here. An excerpt from the Nature overview provides a sense of the scope of current vaccine development efforts:
"As of 8 April 2020, the global COVID-19 vaccine R&D landscape includes 115 vaccine candidates (Fig. 1), of which 78 are confirmed as active and 37 are unconfirmed (development status cannot be determined from publicly available or proprietary information sources). Of the 78 confirmed active projects, 73 are currently at exploratory or preclinical stages. The most advanced candidates have recently moved into clinical development, including mRNA-1273 from Moderna, Ad5-nCoV from CanSino Biologicals, INO-4800 from Inovio, and LV-SMENP-DC and pathogen-specific aAPC from Shenzhen Geno-Immune Medical Institute (Table 1). Numerous other vaccine developers have indicated plans to initiate human testing in 2020."
2/ At least 19 countries have active vaccine development efforts ongoing. Notably, this landscape does not include any efforts in South America or Africa that we are aware of.
3/ There are multiple technical approaches (at least 9 currently described) being pursued including vehicle + RNA (e.g., lipid nanoparticle (LNP) + RNA), naked RNA, naked DNA, adenovirus vector + structural (S) protein, and engineered immunomodulatory cells, specifically dendritic cells (DCs) and artificial antigen-presenting cells (aAPCs). Five of these approaches are now at the stage of Phase I trials.
4/ Each technical approach comes with its own set of experimental/development challenges. For example, in the case of LNP + RNA approaches, there is ongoing concern/debate regarding sub-cellular targeting of RNA messages to the correct location within the cell to be appropriately transcribed as intended in the face of unintended/unrecognized sub-cellular aggregation. In addition, there is debate as to whether singly targeting S protein is sufficient to generate a sufficient immune response. In the case of viral vector-based approaches, considerable work/debate has gone into understanding adjuvant molecular and/or cell-based therapies to, roughly, activate both humoral and non-humoral immune response.
5/ An active open question regarding the development of immunity has to do with what in fact constitutes an optimal immune response. For example, in some cases non-neutralizing antibodies actually can unexpectedly promote viral entry by mechanisms distinct from the already described ACE Receptor-dependent mechanism (e.g., unintended uptake by macrophages and subsequent cellular entry that is counterintuitively promoted by a strong cellular response). Broadly, this is known as Antibody-Dependent Enhancement (ADE). ADE has been described previously in the case of other viruses, most notably Dengue virus. In addition to the possibility of unintended ADE, there is also the need to understand dysregulation of T-cell, or memory-based, responses, so-called Th immunopathology. The risk here is that sub-optimal/non-canonical/faulty T-cell responses can eventually lead downstream to a hypersensitivity-like reaction with local airway inflammation as one of the unintended results and, in more extreme cases, general end-organ damage. Early sequencing data suggests that we are seeing a genome-wide interferon-specific hyper-response at least in some sub-populations that correlates with a faulty local cellular response.
6/ One big takeaway from the current work is that it is likely necessary to understand the immune response as a continuum (i.e., hypo-response to hyper-response) rather than just on/off. Controlling this may require, among other things, an understanding of antibody-virion stoichiometry and kinetics across different cohorts of vaccine recipients (i.e., antibodies that bind less avidly require higher titer to be effective and could thereby induce unintended activation of the complement system; titer is itself often a function of a recipient's pre-existing immune status). This possible shift in equilibrium to hypercoagulable states would correlate with increased incidence of clinical events like pulmonary embolism. Some relevant literature can be found here, here, and here.
7/ Related to the issues noted in note 6/, clinical studies have been directed over recent weeks at understanding other coronavirus family members within the general population as a way to also understand SARS-CoV-2. Findings from a Columbia University study suggest that at least a sub-population of those tested have been re-infected even after seroconversion. Importantly, it is not yet clear whether this is due to an intrinsic factor of a virus (such as its mutation rate) or an extrinsic one like sub-optimal antibody response (e.g., not high enough titer of the antibodies produced on first infection to confer subsequent protection). These findings seem to suggest that understanding the hypo- to hyper-response continuum noted above will be important. This could be done by population-level serum sampling to understand at much higher granularity both the type and intensity of immune responses across various cohorts, with the goal of understanding where in this continuum COVID-19 immunity could actually exist. Such a study is now underway within the NIH.
8/ Taken together, the notes above indicate that several feedback inputs (e.g., genomic testing + longitudinal serum sampling) are needed to inform vaccine development in such a way as to allow us to address both the variance in clinical cases and outcomes currently being observed and the challenges we've previously seen with previous vaccine development efforts such as RSV, Dengue, SARS, and others.
– Dac Nguyen, MD, PhD & Geoffrey W. Smith
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