After more than two long months of social distancing, wearing masks, and working from home, we are all looking forward to life returning to its normal state. But one of the biggest hurdles to overcome for returning to normal social and economic activities in achieving so-called ‘herd immunity for COVID-19’ 

So, what exactly is herd immunity, and what is the quickest way we can achieve it for COVID-19? 

Well here is the bad news, we currently have no vaccines against SARS-CoV-2, and natural herd immunity through infection typically takes decades to achieve. Herd immunity is exactly what it sounds like, it describes the state of a population of people (herd), in which a large segment of that population is immune, either through natural immunity by infection or through vaccination. 

This markedly reduces the virus’ ability to spread through the population (Fig. 1). The percentage of people who need to be immune to effective herd immunity depends on the type of disease and how contagious is it. For a person to person viral infection such as SARS-CoV-2, epidemiologists estimate ≥70% of the population will need to be immune to the virus for herd immunity to become an effective tool against its spread. That might be very hard to achieve without either a lot of people getting sick or an effective vaccine administered across the globe. 

Fig. 1. The Principles of Herd Immunity, Vaccination, and Social Distancing. Without vaccination or social distancing, SARS-CoV-2 would spread rapidly through a population from person to person, creating exponential numbers of infected individuals. Although immunity within the population may be acquired within one round of infection, it is likely that this would result in very high rates of mortality and over-stress the healthcare infrastructure of that population. Social distancing has been effective in flattening the curve of infection and slowing the spread of the virus. Although this prolongs the infection period, it enables healthcare systems to allocate resources more effectively, which ultimately saves lives. The best herd immunity is achieved with the use of vaccines. This provides widespread immunological protection that can profoundly reduce infection rates and associated mortality.

The Swedish approach to COVID-19 herd immunity

Sweden took the most profound steps towards acquiring natural herd immunity compared with other countries (New York Times May 4th, 2020, Coronavirus, and the Swedish Myth). Although mass gatherings and travel were banned, other restrictions were far less severe and as a result, Sweden’s economic-disruption has been far less than experienced in other countries- but not without a price. The country now has the highest fatality rate per capita in Scandinavia, with its older population making up 86% of deaths. By mid-April, Prime Minister Stefan Löfven admitted  "We did not manage to protect the most vulnerable people, the most elderly, despite our best intentions." However, Sweden did manage to prevent their hospitals and ICUs from becoming overwhelmed, and that ultimately saved lives. 

And although recent figures have indicated that 25% of the Swedish population carry antibodies to SARS-CoV-2, that is still well below the 70% needed for herd immunity. However, the country’s governmental and healthcare leaders are planning that this approach will help prevent a second wave of SARS-CoV-2 later this year and that this strategy will help protect the long-term economy of the country.  

Sweden vs the USA: Different responses to the COVID-19 pandemic

So, would the US have been better off taking a similar approach to Sweden’s? Well, probably not. The Swedish population is much smaller than the US, they are overall very active and healthy, and rates of chronic conditions such as heart disease and diabetes that increase risk of mortality from SARS-CoV-2 are much lower in Sweden compared with those in the US. In addition, widely available molecular and serological testing in Sweden were up and running much more rapidly than in the US, enabling those who were infected to self-isolate much earlier, and those who had been exposed to more safely return to work sooner. 

South Korea’s approach to the COVID-19 pandemic

Although ultimately time will tell what approaches best protect any given country, South Korea certainly seems to have turned their situation around very effectively- not through herd immunity but through many lessons learned from the SARS (2003) and MERS (2015) outbreaks. The country has earned international praise for rapidly flattening the curve of SARS-CoV-2 infections through intensive testing, contact tracing, and most importantly through a solid relationship of trust between the government and the people, working together for the common goal of protecting the country’s population. But with so many factors in play, it is still possible that this strategy will not be enough to prevent subsequent outbreaks of SARS-CoV-2 within the South Korean population (The New England Journal of Medicine Editors Note, May 7th, 2020). 

With countries taking very different steps to mitigate the spread of SARS-CoV-2, there is a great deal we can learn that will ultimately help us fight similar outbreaks in the future. Only with longer-term studies will we know the impact (positive or negative) of the different approaches to this pandemic, that will hopefully enable us to learn how to address outbreaks of this severity again.

Global Natural Immunity to COVID-19- A Dangerous Misconception  

As of the first week of April 2020, no country is anywhere close to achieving herd immunity for SARS-CoV-2, in fact, no more than 2-4% of any country’s population has been infected with the virus. When we look at the population of NYC, with the highest infection rate in the US, testing and rough estimates conclude that only 15-20% of the population has been infected. As a result one in 500 of NYC’s population has died. Even though Covid-19 is now the leading cause of death in the USA, there are nowhere near enough of us infected to ensure that natural herd immunity is achieved. To spell it out, without a vaccine, herd immunity in the US would require that 200 million Americans contract SARS-CoV-2, resulting in >500,000 deaths- and with now roughly 25,000 new cases reported every day, we wouldn’t get anywhere close to herd immunity this year.

Do patients who recover from COVID-19 develop long-term immunity?

One of the most significant unknowns with all of this is around how long immunity, either through infection or vaccination, will last for an individual. When a person becomes infected with a virus such as SARS-CoV-2, within a few days the immune system has invoked a response to the virus. Of the three acute respiratory disease-causing viruses, MERS, SARS-1, and SARS-2, the immune response to SARS-1 is most clearly understood. The initial and most prolonged injury from these viruses takes place in the lungs, where the immune response is initiated. For coronaviruses, the immune system key pattern receptors include the Toll-Receptor 7, RIG-1 and MDA-5 and the cGAS-Sting pathway (Shehan et. al., 2008; Zust et. al., 2011; Sun et. al., 2012). Upon activation, these pattern recognition sensors initiate the signaling pathway that expresses type I IFN which is the first step in a cascade reaction to limit viral replication. However, these viruses have evolved multiple immune evasion systems that limit this early production of IFN, enabling the virus to propagate and establish a foothold of infection throughout the body.

Understanding the protective immunity to SARS-CoV-2 is central to the development of effective vaccines and public health initiatives to address this pandemic. Recent studies in rhesus macaques have demonstrated that SARS-CoV-2 infection does in fact induce protective humoral and cellular immunity against re-exposure, and supports the possibility of immunological approaches to the treatment and prevention of this disease in humans. (Chandrashekar et. al. May 2020) 

Similarities and differences between SARS-1 and SARS-CoV-2

Significantly, both SARS1 and SARS-CoV-2 display a paradox in that viral loads are often seen to decline as the severity of the disease continues, which often correlates with an upregulation of proinflammatory cytokines and chemokines (Nikolich-Zugich et. al. 2020). 

Cytokine storms in COVID-19 patients

It is now commonly accepted that many of the most severe cases of SARS-CoV-2 involve cytokine storm, a condition where large numbers of white blood cells are activated to release inflammatory cytokines which in turn activates more white blood cells, creating a positive feedback loop of pathogenic inflammation.  A retro-perspective study of survivors versus non-survivors confirmed an early and sustained pattern of innate immune activation and cytokine elevation (particularly IFN-α, IFN-γ, CXCL10, and CCL2) which does not progress to antibody production, were all associated with increased rates of mortality (Mehta et. al. 2020). It appears that these patients are stuck in a state of hyper-innate immunity, and do not appear to have the ability to progress into an adaptive immune response with the development of antibodies. Although the underlying cause of this innate immunity loop is not fully understood, it has been suggested that the furin protease plays a role in viral pathogenicity for dengue fever and avian influenza (Braun and Sauter, 2019). 

The SARS-CoV-2 virus appears to exploit furin protease activity to enhance cell entry and processing of the virtual particles within the trans-Golgi network, and initial studies indicate that increased baseline levels of furin protease are associated with increased infectivity and pathogenicity of the SARS-CoV-2 and poorer patient outcome.   Characterizing SARS-CoV-2 immune system interactions and effects are critical in driving effective therapeutic intervention both early on to boost the immune system response, and later to scale it down in patients who are at risk of cytokine storm from this infection.  Immunological profiling is now becoming crucial for establishing clinical intervention strategies and best practice protocols in these patients.

Fig. 2. Overview of SARS-CoV-2 infection. Clinical Intervention approaches under different clinical stages, including the worst-case scenario escalation into a cytokine storm. 

Long Term- We need a vaccine for COVID-19.

Even though rapid advances have been made in acute treatments for the most severe cases of SARS-CoV-2, our long-term strategy against this disease undoubtedly lies in the development of safe and effective vaccines. The scientific community is now focusing on innovative strategies to design and refine various vaccine approaches.

COVID-19 vaccine candidates

To date, more than 50 SARS-CoV-2 vaccine candidates are in development, and these fall into several general types:

6 types of potential COVID-19 vaccines

1. RNA-based vaccines. Genetic instructions for the production of the SARS-CoV-2 Spike protein are delivered into cells.  This is a largely unproven technology, that may prove too complex and expensive for global production and distribution.
2. DNA-based vaccines.  The Gene for the Spike protein is delivered into the cell nucleus. These would certainly be less expensive than RNA-based vaccines, but they are also largely unproven, particularly when it comes to older patient immune system responses.
3. Protein Antigen-based vaccines. Focus is now on the Spike protein and the adoption of potent adjuvants for enhanced immunological responses.    
4. Attenuated virus-based vaccines. This is the oldest form of vaccine production, where the virus is exposed to an agent that prevents it from being infective, while still stimulating the immune system.  But there are concerns over safety and the immuno-protection that this would afford, given the mutated forms or strains that are now described.
5. Weakened Virus- Forms of the virus are used that are able to infect cells in order to induce immunity, but weakened enough to not cause the disease. Examples include the vaccines against mumps, measles, rubella, smallpox, and chickenpox.  Many questions over how this could be achieved and how safe this strategy would be in the long run.
6. Virus-like particles, non-replicating, and replicating viral vectors. Harmless or weakened viral systems to carry DNA for the SARS-CoV-2 Spike protein into cells.   

Challenges facing COVID-19 vaccine researchers

Unfortunately, our knowledge and predictive understanding of the immune response is not yet far enough advanced to enable us to accurately foresee vaccine safety and efficacy. So, the current plan of pursuing multiple strategies is ultimately the best approach we can take against this pandemic, and as of the end of March 2020, 10 different vaccines were in phase I clinical trials in the US. There are many challenges ahead though, animal models for SARS-Cov-2 might be difficult to develop since only mice with humanized ACE2 can be infected, and even then, only mild symptoms are induced. 

Other model systems including ferrets and Non-Human Primates are showing more promise, but we have a long way to go with these complex GLP-toxicology and efficacy studies. There are also challenges in large scale production and Quality Control of vaccines, and it is highly likely that any vaccine formulation that demonstrates efficacy will be licensed by various regulatory agencies across the globe in order to maximize production and subsequent access. How this will translate on the global economic stage has yet to be seen, but it leaves many concerned that any effective vaccines will only be available to wealthy nations. 

Fig. 3. Summary of the traditional versus expedited route for SARs-CoV-2 vaccine development and approval. Current timelines are ambitious and unprecedented – but it is under these circumstances that innovation and collaboration can thrive.

How long would it take to develop a vaccine for COVID-19?

The accelerated path of vaccine development that is being pursued SARS-CoV-2 is ambitious, particularly given that the genetically-based RNA and DNA vaccine systems have no proven predicate in humans, and so there is almost no data around their safety in humans, or adaptations available for mass production. A recent publication reporting a study of SARS-CoV-2 Spike protein DNA vaccines in macaques has provided hope that this approach may work in humans  (Yu et al, 20th May 2020) Because of the severity of the current pandemic, vaccine regulators around the world are discussing the fast-tracking of clinical trials (Fig. 3). However, realistically, a vaccine will take 12-18 months or longer to develop and test in the clinic, and today, we do not know if an effective vaccine strategy is even possible for SARS-CoV-2. 

If a vaccine is approved, it will take time to produce, distribute, and administer to the world’s population. And since we have no immunity to this virus, it is very possible that prime-boost vaccination regimens will be needed. An additional factor for consideration is that older populations appear to be particularly vulnerable to SARS-CoV-2, and they often require higher neutralizing titers against infection, so it is possible that various vaccine approaches and adjuvant formulations will be needed to provide effective and affordable immuno-protection across different population demographics (Amanat & Krammer, 2020). Harmonized approaches to vaccine research and  clinical trial testing, followed by  accelerated licensure and distribution are being explored for 

Last thoughts 

With all of this uncertainty in overcoming this pandemic, it can seem overwhelming; but we need to look back and consider exactly what the medical and scientific communities have accomplished over the last few months- we have learned more about SARS-CoV-2 in the last 5 months than we knew about HIV, four years after the initial outbreak. Today we know that COVID-19 disease is caused by a novel coronavirus; we know the genetic structure and infection route of this virus; we have a handle on the epidemiology, access to multiple diagnostic tools and potential therapeutics, along with a growing understanding of the impact of the infection on multiple organ systems. Those facts in themselves are remarkable, a credit to the scientific research community, and a firm indication there truly is hope for breakthroughs.

We have come a long way in a short time. We now require an out-of-the normal, scientifically driven, and coordinated plan to develop, test, produce, and distribute vaccines within months. This can only be achieved with the commitment and collaboration of our governments, regulatory agencies, pharmaceutical, and biotechnology companies, along with trustworthy oversight by the World Health Organization. There are so many political and social lessons to be learned through all of this, but the global scientific community has shown an uncompromising commitment to the greater good, and as a scientist that is truly inspiring to see.   

References

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Zust R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, Szretter KJ, Baker SC, Barchet W, Diamond MS, Siddell SG, Ludewig B, Thiel V. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol. 2011;12:137–143. doi: 10.1038/ni.https://www.ncbi.nlm.nih.gov/pubmed/21217758 

Sun L, Xing Y, Chen X, Zheng Y, Yang Y, Nichols DB, et al. Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS One. 2012;7:e30802. 10.1183/13993003.0040. https://www.ncbi.nlm.nih.gov/pubmed/22312431 

Chandrashekar, A., et. al. SARS-CoV-2 infection protects against re-challenge in rhesus macaques. Science 10. 1126. May, 2020.

Nickolich-Zugich, J., Knox, K.S., Rios, C. T., Natt, B., Bhattacharya, D., and Fain, M. J.  SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. GeroScience 2020 April 10:1-10 PMCID: PMC7145538. https://www.ncbi.nlm.nih.gov/pubmed/32274617 

Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S. COVID-19: consider cytokine storm syndromes and immunosuppression. 2020 The Lancet vol. 395 (10229) p 1033-1034. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext

Amanat, F. and Krammer, F. SARS-CoV-2 Vaccines: Status Report. Immunity 2020 PMCID: PMC7136867; PMID: 32259480. https://www.ncbi.nlm.nih.gov/pubmed/32259480

Authored by: Dr. Julie Bick

Dr Julie Bick is a medicinal biochemist who has spent close to 7 years with FlowMetric Life Sciences. After receiving her doctorate in Biochemistry at Southampton University in the UK, she began her career as Associate Professor at Rutgers University, NJ, before moving to the west coast to perform biomedical research with Syngenta and Novartis at the Tory Mesa Research Institute in San Diego. Dr. Bick specializes in biomedical engineering of cells and proteins in order to provide innovative therapeutic and diagnostic solutions. She brings to FlowMetric a clinical expertise across a wide range of therapeutic areas from autoimmunity to oncology and chronic inflammatory conditions, acquired over 25 years of research experience in academic, biotechnology and pharmaceutical laboratories. In leading FlowMetric Life Sciences’ innovation initiatives, Dr. Bick has been collaborating with BurstIQ to implement Block Chain solutions into the company’s Contract Research Organization division, with a focus on enhanced big data analytics and process control solutions in the regulated clinical environment. Dr. Bick is committed to working with local Community Colleges to support STEM programs for the next generation of scientists.