Herd Immunity – Can We Get There?

The concept of herd immunity is frequently brought up as an alternative to lockdown and intervention-based strategies for curbing the COVID-19 pandemic, this sensitive issue being much influenced by policy makers. In this context it is important to first define herd immunity. This is obtained when enough of the population has immunity to an infectious pathogen, thus resulting in prevention of its transmission. The clearest examples of achieving herd immunity are provided by successful vaccination programs (i.e., polio, smallpox and measles). The question of whether acquisition of herd immunity to SARS-CoV-2 is possible depends upon important questions. How long will it take to get such herd immunity? What will be the cost in human deaths? Will there be a successful vaccine program? And does infection provide a lasting immunity for further prevention of reinfection?

Let’s first consider the possibility of obtaining herd immunity by vaccination. Ideally, strong herd immunity can be achieved if a vaccine provides a very significant (say around 80-90%) protection (sterilizing immunity) for extended periods, and if most of the population has been vaccinated. However, it is currently uncertain that these conditions will be met. A recent survey conducted in 19 countries showed that approximately, 70% of participants were likely to take a SARS-CoV-2 vaccine(1), indicating that public acceptance will by no means be universal. Assuming such a vaccine were 70% effective, this would leave 50% of the population able to be infected. Interestingly, if a vaccine were government mandated, acceptance dropped to 50 to 60%. Obviously if we are trying to reach herd immunity by vaccination, vaccine efficacy and acceptance will be critical.

Is it possible that natural infection of a large percentage of the population would result in widespread immunity? This could in theory lead to a reduction in further viral spread to the point where it would become relatively insignificant. This depends, however, upon several factors. First, is that a large proportion of the population would need to be infected. Given an estimated infection mortality rate of 0.3 to 0.5%, this would likely result in an unacceptably high number of deaths. Second, how long would it take? Indeed we know that beside some areas such as New York or Paris for example the percentage of infected individuals has apparently remained quite low (10-15%). Third, infection would need to lead to reasonably durable immunity, and we will consider this in more detail.

As to whether infection confers immunity, this is complicated by not knowing the levels of protective immunity to SARS-CoV-2. Inducing neutralizing antibodies have been a major target for development of many vaccines based on the evaluation of immunity to other coronaviruses. Importantly, evaluation of the rate of reinfection can predict a potential acquisition of protective immunity by natural infection. Reinfection is not necessarily proven by the second positive diagnostic to SARS-CoV-2; there is a question of whether the patient has truly become reinfected or the original infecting virus has simply rebounded.

The answer seems to be that reinfection does occur but is quite rare. Indeed, there are only a handful of well documented cases showing reinfection with SARS-CoV-2. In one well characterized instance, a patient was asymptomatically reinfected 4-5 months after a first symptomatic infection(2). Viruses from the first and second infections were phylogenetically distinct, indicating that they were independent infections. Interestingly, although neutralizing and IgG antibodies were not detectable at the onset of the second infection, they rapidly and robustly appeared (3). A handful of other cases have been reported.  However, their relative rarity suggests that reinfection is the exception rather than the rule. What, then, are the potential protective mechanisms and how long do they last?

The short answer is that we don’t have exact answers yet. Much attention has focused on antibody response and durability, particularly on antibodies to the spike protein and neutralizing antibodies (NA), which are a subset of the anti-spike antibodies. Both anti-spike and neutralizing IgG (but not IgM and IgA) antibodies decrease but persist at measurable levels for at least three to six months after the resolution of the infection. Indeed, anti-spike and NA correlate reasonably well with protective immunity ((4, 5) and these two studies). and. Moreover, as mentioned above, priming by memory cells can result in rapid and robust expression of antibodies. One study showed that a better correlation between NAs and spike antibodies could be obtained by measuring NAs and both anti-receptor binding domain (RBD) and S2 domain antibodies(5). However, it is unclear what level of NAs would be protective against SARS-CoV-2 infection.

It is likely that T cell activity will be necessary for significantly durable immunity. T cell activity is more difficult to assess than antibody response, and correspondingly less is known for its role in lasting protective immunity. We should point out that some patients who have recovered from mild COVID-19 and are PCR negative for SARS-CoV-2, show T cell activity against viral peptides even though they were antibody negative(6), suggesting the involvement of cell-mediated immunity. A strong T cell cytotoxic response is evident during disease, and in the convalescent phase, a memory T cell response is common even in the absence of antibodies(7). This suggests that immune responses will be durable, although this is not yet known for SARS-CoV-2.

Many immunologists are still evaluating a lasting immunity to SARS-CoV-2.  No matter what, infecting a substantial majority of the population to reach herd immunity would likely result in a massive death toll. For example, in the U.S., probably one to two million people would die. In addition, we need to consider serious medical and financial consequences for ill individuals with COVID-19. Further, many people who have recovered from the virus report lingering health effects. Earlier in the pandemic, Sweden was pursuing a herd immunity strategy by essentially relaxed containment; yet that strategy has led in June and July 2020 to the highest rate of death in Northern Europe.

Overall containing the pandemics will not be the result of a single intervention; it will combine efficient prevention measures, novel preventive and curative treatments as well as sufficiently effective and safe vaccine. In any case, waiting for spontaneous herd immunity does not appear as a reasonable option for the population.

1. J. V. Lazarus et al., A global survey of potential acceptance of a COVID-19 vaccine. Nature Medicine, (2020).
2. K. K. To et al., COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis, (2020).
3. K. K. To et al., Serum antibody profile of a patient with COVID-19 reinfection. Clin Infect Dis, (2020).
4. A. S. Iyer et al., Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Sci Immunol 5, (2020).
5. T. J. Ripperger et al., Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. medRxiv, (2020).
6. S. Schwarzkopf et al., Cellular Immunity in COVID-19 Convalescents with PCR-Confirmed Infection but with Undetectable SARS-CoV-2-Specific IgG. Emerg Infect Dis 27, (2020).
7. T. Sekine et al., Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19. Cell, (2020).
8. N. Le Bert et al., SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584, 457-462 (2020).