Many of the public via mass media channels believe that the present vaccination strategy embarked upon by majority governments and their health authorities, academic medical centers and the life science industry will bring societies back to pre-pandemic normalcy. That’s why there are daily counts of the number of inoculations against COVID-19 by nation, region, state and even by city in some places. A publicly reported mass vaccination that all believe lead us back where we started, a normal, happy time, is reinforced by the research investment patterns of agencies and institutes, such as those in the U.S. that have spent far more billions on vaccines than on therapeutic interventions, such as prophylaxis, for example. At each and every juncture during the pandemic, the public’s belief is in vaccination as an absolute key to the end of the crisis. Emerging new norms will reinforce this paradigm, such as travel vaccination passports introducing not only not before conceivable impediments to human movement but positive reinforcement for vaccination status. But what if this was just part of an answer? What if actually the introduction of therapeutics serving as prophylaxis as well as other ways to reduce risk were just as important in helping societies not only get COVID-19 under control but also overtake the pathogen? While new research from a group of scientists from both academia and the private sector suggests that a vaccination-mediated reduction of transmission is key for elimination of SARS-CoV-2, the virus behind COVID-19, it should be combined with complementary interventions.
Recently uploaded to the preprint server known as MedRxiv, a group of New England and San Diego-based researchers out of Boston University, Boston Medical Center, Dartmouth, Fractal Therapeutics and Halozyme Therapeutics utilized sophisticated epidemiological modeling framework to support and facilitate a better understanding between vaccine characteristics and effectiveness in helping society finally overcome the COVID-19 pandemic.
“Have you gotten your vaccine yet?” is repeated countless times in social circles around good parts of the world now. Even in low-to-middle income countries (LMICs) the topic ranges among elites to the professional classes via prominent media disseminated throughout particular societies.
The societal emphasis on a vaccination first strategy—formulated by a combination of government health authorities and institutes as well as regulators, academic medical centers and major research institutes and importantly industry—is continuously reinforced by intense lobbying or promotion to the public via the plethora of channels and outlets, from major media and rapidly consolidating local media channels to the often curated social network news and information to schools and universities and employers, vaccination first is clear and evident.
The National Institute of Health (NIH) established ACTIV to serve as a public-private partnership supporting, among other things, direct research dollars to clinical trials. TrialSite has meticulously tracked federal spend directed into vaccines versus therapeutics and other approaches, and many billions more have gone directly to just a handful of vaccine developers. That is, a vaccine-first strategy is reflected in the pandemic response investment patterns directed by the NIH, industry, etc.
Moreover, when emphasis is on therapeutics or other approaches, the spending of taxpayer money greatly emphasizes novel, advanced (and expensive) branded approaches over drug repurposing, which TrialSite attributes to the drug development incentivization system itself.
The authors behind this recent research, not yet peer reviewed, acknowledge that “the experiences of 2020 have shown that the basic reproduction number (R0) and capacity of pre-symptomatic spread make SARS-CoV-2 difficult to control once it is established within a population.”
The team notes that of course the development of efficacious vaccines represents a fundamental underpinning in the effort to overcome the disease, ones that “prevent colonization of the nasal cavity, symptomatic disease, severe disease, mortality or transmission.” But the authors convey that for the current crop of vaccine products, the clinical trials’ primary endpoint involves “symptom-gates efficacy” that is “where cases are counted as patients presenting with symptoms of COVID-19 and SARS-CoV-2 infection confirmed by nucleic acid amplification test.”
But vaccine-based elimination strategies targeting SARS-CoV-2 face a number of challenges due to challenging actual characteristics of the disease. The authors include the following characteristics:
· Waning nature of both natural and vaccine-mediated immunity
· Potential for vaccinated individuals to transmit the disease
· Age-dependence of both disease severity and possibility of vaccinal immunity
· Potential for emerging resistance
Waning of Natural & Vaccine-Mediated Immunity
The authors back their claim of waning natural immunity based not only on the behavior of other coronaviruses but also as recently evidenced for cellular and humoral immunity in response to the disease. They posit that a number of reinfection cases are proven using “direct molecular techniques.”
Does relative short-term immunity serve to disrupt assumptions for the current disease control model by “limiting the duration of natural herd immunity and providing the virus with a foothold even in populations that have previously experienced a high attack rate?”
Again, the authors put forth that waning of vaccinal immunity over time introduces a potentially insurmountable logistical burden if the approach to overcome the pandemic isn’t bundled with other approaches, such as prophylaxis.
Asymptomatic Transmission by Vaccinated but Colonized Individuals
Another risk characteristic of SARS-CoV-2, suggests the authors, is the “asymptomatic transmission by vaccinated but colonized individuals.” They make the case using a number of examples that evidence exists that those asymptomatic can in fact be contagious. According to select contract tracing sources, presymptomatic and asymptomatic individuals are responsible for 50% of all COVID-19 transmission events.
Their position—those individuals that have SARS-CoV-2 colonized in the nasal cavity will likely present asymptomatic and thus will be contagious, that is able to pass the disease on to others. Of course, the overall transmissibility is less intense and severe but nonetheless renders the goal of her immunity more elusive.
For every 20 years of age, the death rate associated with COVID-19 rises by an order of magnitude from about 0.013% at 25 years old to 8% at 85 years. Arguing that a number of other diseases evidence age-dependent reductions in vaccine efficacy, the research team suggests that in the case of at least some of the COVID-19 vaccines, “peak antibody titers” in the elderly 65 and up “appear to be lower relative to younger” individuals that have been inoculated.
They acknowledge that actual vaccine efficacy by age subgroup isn’t sufficiently understood as of yet due to clinical trial sample size and study design issues.
Due to widespread far reaching COVID-19 infection and circulation within the global population, favorable breeding opportunity surfaces for immune evasion mutants. While sequencing initiatives evidence material variation for the viral spike protein—and other surface proteins—the researchers point out that human “immune response is narrowly targeted, with the epitopes for RBD-targeting neutralizing antibodies overlapping one another substantially.”
The nature of this pathogen is such that a number of variants with ACE2 affinities evidence “infection-competence in-vitro, suggesting low fitness cost by the virus in evading the immune response.”
They point out that their models mirror real-world unfolding dynamics, where variants such as 501Y.V2, (South Africa) can actually “complete immune escape from therapeutically relevant monoclonal antibodies, as well as convalescent plasma.”
The Key Argument
The four points above lead to a set of real-world constraints attached to any COVID-19 elimination scheme based primarily on vaccination in a quest to get back to normalcy.
Compliments are Needed in Parallel
The authors suggest “stacking interventions” from “indoor air filtration” to “prophylactics” to augment the fight against COVID-19, helping to “broaden the range of vaccine efficacy moving forward. They don’t delve into details beyond that.
TrialSite suggests, of course, this raises differing interpretations. Many front line doctors and a growing number of researchers call for the need for treatments that help reduce the severity of the illness while reducing transmission. Depending on population cohort and associated risk, various strategies are employed with a mix of vaccine, treatment and other measures (protective equipment, etc.).
A number of studies around the world, for example, have produced evidence that generic repurposed drugs have a real place in the mix of treatment approaches along with vaccines that stop infection and/or transmission.
Of course, prominent pharmaceutical companies also in some cases have received hundreds of millions of taxpayer dollars to develop prophylaxis: for example, AstraZeneca’s AZD7442. Repurposed therapies from ivermectin to favipiravir and fluvoxamine as well as other candidates targeted should be considered as well.
Moving forward, mission-critical public health metrics include rate of infection and viral load (predictor of transmissibility) and could even outweigh the importance of the number of total symptomatic cases, suggest the authors.
· Madison Stoddard, Fractal Therapeutics, Cambridge, MA
· Sharanya Sarkar, Department of Microbiology and Immunology, Dartmouth College, Hanover, NH
· Ryan P. Nolan, Halozyme Therapeutics, San Diego, CA
· Douglas E. White, Independent Researcher
· Laura F. White, PhD, Department of Biostatistics, Boston University, Boston, MA
· Natasha S. Hochberg, MD, MPH, Boston University, Boston Medical Center
· Arijit Chakravarty, CEO, Fractal Therapeutics, Cambridge, MA