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Breakthrough Cases of Covid-19

Posted on: August 05, 2021


What are they, and what are their immediate and long-term implications in the United States and Globally?


What exactly is a so-called ‘breakthrough case’ of Covid-19 infection?

Even early this year, before vaccines were being widely rolled out, very low numbers of so-called breakthrough cases- Covid-19 diagnoses in vaccinated individuals, were reported. Over the past few months however, there has been a significant increase in the prevalence of described breakthrough cases, and some of these patients are reported to present significant and long-term symptoms. As we begin to unravel the emergence of variants of the virus, we can better understand the limitations of the current first-generation SARS-CoV-2 vaccines and how this relates to the breakthrough phenomenon, along with its implications for public health through this pandemic.

Even now, there is some debate as to how we apply the term ‘breakthrough case’- with some public health officials reserving the term only for severe case of Covid-19 in the vaccinated population and pointing to the efficacy of the current vaccines to prevent the development of severe symptoms. How-ever the term is defined, breakthrough cases have the potential to prolong this pandemic and long-term strategies will now have to involve understanding the underlying factors behind these cases, and the role of viral evolvement and selection in potentially undermining vaccine efficacy.

So just how prevalent is the breakthrough phenomena? As of June 8th, 2021, the Centers for Disease Control (CDC) reported that among 140 million fully vaccinated individuals, 3,300 hospitalizations, and 1 death for every 230,000 were confirmed within this cohort. A study in Israel described similar patterns but suggested that mild- or asymptomatic cases may be significantly higher than currently confirmed, and that in all reported deaths from Covid-19 in the vaccinated population, we associated with comorbidities, with > 40% being immuno-compromised (Brosh-Nissimov et. al. 2021).

What factors are involved in the increasing number of breakthrough cases?

Do we know what is driving this this breakthrough phenomena? Well, there are a number of diverse factors that have resulted in more than expected or predicted cases of symptomatic Covid-19 infections in our vaccinated population. The most recent studies from the UK and Israel all demonstrate the enhanced overall effectiveness of the mRNA-based vaccines versus the adenovirus-26-Johnson & Johnson vaccine. Since most of us didn’t have a choice of vaccine, this is a difficult factor to address, however, increasing statistics around vaccine efficacy will certainly impact the adoption of boosters as well as help address long term global vaccination goals. The Food and Drug Administration (FDA) and CDC are now considering Pfizer’s EUA application for the use of booster shots for those over 65 years of age and the immuno-compromised, although how and when this would be rolled out is still unclear.

In many states, less than 50% of the population has been fully vaccinated, and so outreach is needed to help push those numbers towards the 70-80% vaccinated population targets. This will require buy-in on a local level, with increased access to vaccines coupled with improved understanding of the personal and public health consequences of vaccination.

Other factors behind this breakthrough infection phenomena involve our return to social mixing and increased mobility, and the relaxing of some of the public health policies such as the wearing of face masks, social distancing, and the limiting of social gatherings. Sadly, this has become a political issue, and although some local governments have reversed their policies and are now re-mandating of face masks in doors including Los Angeles and the Bay Area, and more recently the state of New Jersey reverse previous guidelines and now is recommending the wearing of face masks by even fully vaccinated people when inside. However other states such as Florida have barred local mask mandates altogether, even though rates of Covid-19 cases are on the rise.

But by far the most significant driver of breakthrough infections has been the emergence of the Delta variant- a form of the virus that is highly contagious compared with the original alpha variant, particularly among unvaccinated people, but has also been showing up in a disproportionate number of breakthrough cases.

Surprisingly, despite the rise of Delta-SARS-CoV-2 across countries with highest vaccination rates (including the UK, Israel, and the US), in May 2021 the CDC decided to no longer track breakthrough cases of infection of vaccinated personnel. They are however building models through carefully designed surveillance systems that are routinely used to track the annual flu.


So how is the Delta Variant Different?

The SARS-CoV-2 B.1.617 lineage was first described in India in October of 2020. Since then, this variant has rapidly become the dominant form of the virus across many regions of the globe. There are currently, 3 main subtypes (B.1.617.1; B.1.617.2; B.1.617.3) that have emerged with different mutations within the Spike protein N-terminal- and Receptor binding domains. These mutations appear to have profound effects on the spread of SARS-CoV-2. Patients infected with these variants have much higher viral loads (~1250 fold that of the original virus, Li et. al 2021) and remain infectious for prolonged periods of time, both factors of which contribute to much higher levels of transmissibility resulting in a significantly more contagious infection. One key mutation is E484K which lies directly within the ACE2 binding region of the RBD; this creates a change in charge that is associated with increased affinity between the Spike protein and ACE2 that appears to increase the ability of the virus to attached and enter cells. Furthermore, these variants have reduced sensitivity to antibody neutralization established either by previous infection or vaccination (Planas et. al. 2021), which means that now more than ever, the USA is at a tipping point in the fight against this pandemic. Estimates of vaccination rates for herd immunity based on the contagiousness of the original viral variants were in the region of 70-80%-with the Delta variant, this number may be much higher, and potentially unachievable globally.

SARS-CoV-2 Diagram

Since unvaccinated individuals are most at risk of this new Delta variant, it currently represents a much higher risk in the disproportionately unvaccinated regions of the Southern and Appalachian US states. Another key consideration is the ability of the Delta variants to infect younger individuals, for whom current vaccines may not even be approved under the EUA. This could result in so-called hyperlocal outbreaks as children return to school in the fall.

There is some evidence that unvaccinated patients infected with the Delta variant have overall poorer outcome than those infected with the original virus, however at this point there are too few studies conducted to clinically resolve this point definitively. What is known is that vaccinated individuals who contract the Delta variant do much better than unvaccinated and are unlikely to need hospitalization.


Are Other Variants Inevitable?

The WHO is currently tracking the emergence of different mutations although distribution of data to researchers is still a challenge and his holding up critical research in this area. Obviously, as the pandemic continues, particularly with such large number of patients infected, it is inevitable that further variants will emerge, and it is likely that new vaccines will need to be developed to address these new forms of the virus. How the increased reproductive efficiency of the Delta variant will affect the rate of future variant emergence has yet to be determined. But one thing is clear, we need to get a firm handle on Delta before it is too late and even more virulent or deadly forms of SARS-CoV-2 emerge.

Earlier this year the US Department of Health and Human Services established a SARS-CoV-2 Interagency Group to help coordinate the transfer of information between the Centers for Disease Control and Prevention (CDC), National Institute of Health (NIH), Food and Drug Administration (FDA), Biomedical Advanced Research and Development Authority (BARDA) and Department of Defense (DoD). Part of the group’s work is to identify and classify variants according to their infectivity.

  • Variants of Interest (VOI) covers all forms of the virus that are being monitored in the US, including their transmission rates, sequence surveillance, drug efficacy studies. There are currently > 50 variants in this category.
  • Variants of Concern (VOC) includes all those that are being closely monitored by federal agencies, where there is evidence of increased transmissibility, disease severity, or a significant reduction in neutralization by antibodies generated during previous infection or through vaccination, or the reduced effectiveness of drugs, vaccines or diagnostic detection. Variants currently listed in this category include the Delta variants B.1.1.7; B.1.351; B1.617.2 and P.1 (out of Brazil).
  • Variant of High Consequence (VOHC) would represent variants that have developed mechanisms to evade medical counter measures such as effective diagnostic testing, reduced vaccine effectiveness or susceptibility to therapeutics. There are currently no SARS-CoV-2 variants in this classification.


Are current therapeutic treatments good enough?

As of today, the FDA has cleared the use of three SARS-CoV-2 monoclonal antibody treatments under the Emergency Use Authorization for the treatment of Covid-19: Eli Lilly’s bamlanivimab plus etesevimab; Regeneron’s sotrovimab, and casirivimab plus imdevimab.

Lab studies have shown that certain substitutions in the Spike protein are associated with reduced therapeutic effectiveness with the first of these treatments, and to date, there is no reported reduction in the susceptibility of variants to sotrovimab. The efficacy of convalescent serum is very difficult to monitor since there is no standardization for this type of therapy.

Despite major efforts by drug development companies, therapeutic options for Covid-19 patients are still very limited. The use of monoclonal antibodies appears to be the most effective therapeutic approach, potentially coupled with the antiviral drug remdesivir.


So, what’s next?

Well vaccination is still our best protection against this virus. Originally, we were all happy to hear that all three vaccines provided outstanding protection against SARS-CoV-2, and that hasn’t changed. Almost all hospitalizations and deaths in the UK and US associated with the Delta variant are in the unvaccinated population. But the unfortunate truth is that the enormous number of infections has enabled the virus to mutate rapidly through a process known as positive selection, which has been demonstrated within both the Spike and Nucleocapsid viral proteins. Such mutations include the D614G and E484K mutations of the Spike protein RBD appears to boost infectivity, by increasing the affinity to the ACE2 receptor, and other RBD mutations N501Y, N234Q, L452R, A475V and V483A that appear to confer resistance to neutralizing antibodies (Boni et. al. 2021).

The evolution of SARS-CoV-2 has largely been shaped by inclusive factors such as the increased viral fitness and infectivity through positively selected amino acid substitutions. Unfortunately, as a now global pandemic (200 million confirmed cases- the real number may be 10 times this, and 4,200,000 confirmed Covid-19 deaths) there will inevitably be continued diversification of the virus within specific geographical regions and the resulting formation of stable, diverging variants. This has the potentially to substantially prolong the pandemic and require modification of the vaccination strategies, possibly extending over the course of the next few years.

Our hope lies in the incredible effectiveness of the vaccines available under the EUA, as well as the strong pipeline of vaccines in development. Waiting in the wings for EUA approval is the Novavax vaccine, that according to the manufacturer is providing 100% vaccine efficacy against the original alpha variant and 93% efficacy against the emerging variants including Delta. Unlike the mRNA and DNA - vaccines, this vaccine is based on more traditional technology, using viral proteins generated in large bioreactors, coupled with adjuvants to stimulate the immune system. Since there are more wide-spread manufacturing plants capable of generating this type of medical product, it is likely that this vaccine or type of vaccine will be adopted for longer-term strategies to vaccinate in developing regions of the world. The fact that this initial version is displaying such high efficacy even against the Delta and Lambda variants is highly encouraging.

Although reverting to social distancing, coupled with the use of face masks, good handwashing practices etc. will certainly help, vaccines remain our strongest tool in this pandemic. At this point, the original vaccines appear to help keep even Delta variant-patients out of the hospital. However, breakthrough cases may still be sources of infection to the unvaccinated and provide a pool for the virus to further diverge. Couple this with the unknown long-term ramifications of Covid-19 and we may be looking far into the future before life can really return to normal.

One way we can ensure optimum and responsible application of vaccines is through immuno-monitoring of anti-SARS-CoV-2 antibodies and help determine when booster shots might be best applied and to whom within the population. FlowMetric is at the forefront of this type of testing with our multiplexed VaxEffect™ test for SARS-CoV-2. Now that some vaccine mandates are being proposed for employees of the Veterans Association, as well as corporation including Facebook, Google and Netflix (https://www.cnn.com/2021/07/29/investing/companies-vaccine-requirement-delta-covid/index.html ), using tests like VaxEffect to demonstrate vaccine effectiveness at a personal level, may certainly help alleviate some of the fears and reticence around the use of these vaccines.

What is clear is this is a marathon, not a sprint, and the effective global monitoring of variant emergence, coupled with wide-spread, global distribution of these safe and effective vaccines will be needed before we can begin to recover from the pandemic return to normality.





Brosh-Nissimov, T. et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully-vaccinated hospitalized COVID-19 patients in Israel. Clinical Microbiology and Infection. (2021). https://doi.org/10.1016/j.cmi.2021.06.036, https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00367-0/fulltext


Li. B. et. al. Viral infection and transmission in a large well-traced outbreak caused by the Delta SARS-CoV-2 variant. Virology.org



Planas, D. et. al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. https://doi.org/10.1038/s41586-021-03777-9 (2021)


Boni, M. F. et. al. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID19 pandemic. Nature Microbiology vol. 5. 1408-17. https://doi.org/10.1038/s41564-020-0771-4


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