Herd immunity is the inability of infected people to cause an epidemic due to lack of contact with a sufficient number of people susceptible to infection. Herd immunity occurs when a large enough part of the population is immune to the disease. Herd immunity can be formed as a result of natural infection or vaccination.

The elimination of smallpox and the steady decline in the incidence of disease among adults and those who have not received routine vaccination with the conjugated Hemophilus b vaccine and pneumococcal vaccine are successful examples of herd immunity formed through immunization.

The threshold of herd immunity

Herd immunity threshold is the percentage of people who have acquired immunity and are no longer involved in the transmission chain. If the proportion of immune people exceeds this threshold, outbreaks will stop, and pathogen transmission will be controlled. The point for herd immunity is reached when an infected person infects less than one person on average.

In the simplest model, the herd immunity threshold depends on the basic reproductive number R⁰ – the average number of people infected by an infected person in a fully susceptible population. The threshold for herd immunity is calculated as 1-1/R⁰. The significant reproductive number characterizes partially immune populations and takes into account changes in the proportion of people susceptible to infection during an outbreak or after mass immunization.

Highly infectious pathogens such as measles will have a high R⁰ (12-18). To reduce the spread of the virus, a significant part of the population must be immune. For SARS-COV-2, the reproductive number is in the range of 2 to 3. If there is no herd immunity, and all people are equally susceptible and equally contagious, the threshold for herd immunity for SARS-CoV-2 is 50 to 67% in the absence of any intervention.

Duration of protection

For both natural and vaccine-generated immunity, immune memory’s stability is a critical factor that supports herd immunity and determines protection at the population level.

In measles, chickenpox, and rubella, long-term immunity is achieved through both infection and vaccination. For seasonal coronaviruses, persistent immunity was not observed or was short-lived. In the case of disorders that cause temporary immunity, the proportion of susceptible people soon increases in the absence of a vaccine, and outbreaks of infection recur.

Herd immunity can be maintained with a vaccine and an effective vaccination program, even if it requires periodic vaccination.

The role of heterogeneity

The nominal threshold of herd immunity assumes random interaction between people. However, in reality, people interact not by chance, and some people have more contacts than others. Empirically validated network models have shown that those with more connections become infected earlier during outbreaks. It can slow the spread of infection in the population until the nominal threshold of herd immunity is reached. However, it is unclear how heterogeneity in social interaction affects herd immunity against SARS-CoV-2.

Cross-reactivity of T cells

T cells are essential immune mediators. They recognize and destroy foreign antigens. Cross-reactivity of a T cell is the ability to provide immunity to several foreign proteins. It saves the body’s resources since it requires far fewer T cells to scan an infected cell than if each T cell recognized only one pathogen. On the other hand, since multiple T cells can recognize the same foreign protein, it is more difficult for pathogens to evade immune recognition. Therefore, cross-reactivity makes the immune defense more effective.

Cross-reactive immune memory for SARS-CoV-2 is primarily due to the previous contact with circulating cold coronaviruses. Recent research has shown that cross-reactivity with other coronaviruses can provide relative protection to the population from COVID-19.

It is unlikely that T cells’ cross-reactivity can form a sterilizing immunity in which a person cannot carry or transmit infection. But cross-reactivity reduces the severity of the disease and may explain the asymptomatic course of COVID-19.

Cross-reactive memory T cells for SARS-CoV-2 are detected in approximately 28-50% of people who have not had SARS-CoV-2. Studies found that cross-reactive CD4⁺ memory T cells (t helper cells) in blood samples, but CD8+ memory T cells (t killer cells) were much less common. T-helpers recognize the pathogen and promote the production of antibodies. T-killer cells recognize and destroy infected cells.

Memory T cells can be classified according to their anatomical location and movement patterns:

• Recirculating Central memory T cells (T_CM) and effector memory T cells (T_EM) travel through the blood and lymph nodes and are recruited to infection sites by inflammatory signals.
• Tissue-resident memory T cells (T_RM) are permanently located in this non-lymphoid tissue, such as in the lungs or upper respiratory tract.

T_SM and T_HE more slowly respond to infections than T_RM cells and usually undergo proliferation several days before entering infected tissue.

CD4⁺ T cells can also be divided into separate functional subtypes:

• T-follicular helper cells (T_FH) are necessary to help B-cells form neutralizing antibodies.
• T-helper cells 1 (T_N1) and CD4 cells with cytotoxic activity (CD4-CTL) have direct antiviral activity in infected tissues.

CD4⁺ T cells provide the immune memory response to the virus. T_FH, T_H1, or CD4-CTL cells may participate in the reaction.

Notably, CD4⁺ T cells do not usually prevent infections by themselves. Instead, they reduce the severity of the disease, reduce the viral load, or limit the disease’s duration.

As for potential cross-reactive humoral immunity, it has been found that circulating antibodies directed at the SARS-CoV-2 spike protein are rare in people who have not had SARS-CoV-2. In particular, cross-neutralizing antibodies are very rare. Animal studies have shown that neutralizing antibodies are Central to antibody-mediated protection against SARS-CoV-2 infection.

Effect of cross-reactive CD4⁺memory T cells on SARS-CoV-2 transmission and herd immunity

Four scenarios for the impact of memory T cells on COVID-19 severity and transmission:

1. Reducing the load on the lungs

Cross-reactive CD4⁺ memory T cells reduce the severity of COVID-19 and viral load in the lungs but cannot eliminate the virus from the upper respiratory tract faster than the primary immune response. CD4⁺ T_CM / T_EM, T_RM, and T_FH may participate in this form of partial protection. The population of cross-reactive memory T cells is relatively small during infection. The response after the infection is relatively slow, and the response of CD4⁺ memory T cells cannot control the viral load of the upper respiratory tract without the involvement of other mechanisms of the adaptive immune system.

Consequences for people

Results for people infected with SARS-CoV-2 who already have cross-reactive CD4⁺ memory T cells compared to infected people without such memory:

• the severity and duration of the disease are reduced;
• there is no change in the viral load in the upper respiratory tract;
• compared to people without pre-existing cross-reactive cells, immune memory generation is unchanged.

Epidemiological consequences

Results for a population with a large number of people with pre-existing cross-reactive CD4⁺ memory T cells, compared to a community with fewer people with such memory:

• lower probability of hospitalizations and deaths from SARS-CoV-2;
• virus spread is unchanged. An increase could occur if the reduction in symptoms made it more difficult to detect and track infection, thus increasing the frequency of undiagnosed cases without reducing infectivity.

2. T_FH accelerates antibody production

Cross-reactive memory T_FH cells cause a faster and stronger neutralizing response of antibodies against SARS-CoV-2 than would occur in the absence of memory T_FH cells. It increases the control of the virus in the upper respiratory tract and lungs. Data consistent with scenarios 1 and 2 were obtained for influenza.

Consequences for people

Results for people infected with SARS-CoV-2 who already have cross-reactive CD4⁺ memory T cells, compared to infected people without such memory:

• the severity and duration of the disease are reduced;
• the viral load of SARS-CoV-2 in the upper respiratory tract will not be affected during the pre-symptomatic phase but will decrease later;
• a reliable immune memory is likely to be created.

Epidemiological consequences

Results for a population with a large number of people with pre-existing cross-reactive CD4⁺ memory T cells, compared to a community with fewer people with such memory:

• fewer hospitalizations and deaths from SARS-CoV-2;
• a moderate reduction in the virus’s spread, as the pre-symptomatic period, plays a significant role in the spread. A reduced viral load in the upper respiratory tract means that the spread of infection will decrease moderately in a population where cross-reactive T cell memory was shared;
• there is considerable heterogeneity in contagion-provided that a minority has such cross-reactive memory. The heterogeneity of infection increases the chance that a virus introduced into a population will not cause a major epidemic.
• 3. T_RM Cells restrict viral replication in the respiratory tract

Cross-reactive CD4⁺ T_RM cells in the focus of infection allow rapid control of the virus in the upper respiratory tract and lungs. These CD4⁺ memory T cells limit virus replication in the upper respiratory tract in the first days after infection. They may also restrict the virus’s repetition due to the rapid activation of the innate immune system.

In the case of SARS-CoV, an intranasal vaccine designed to induce CD4⁺ T cell responses has activated CD4⁺ T_RM cells in the respiratory tract. These cells provided significant protective immunity in mice, but the protection was directed against death and did not prevent early replication of the SARS-CoV virus. CD4⁺ T_RM cells eliminated virus replication for ~5 days.

Consequences for people

Results for people infected with SARS-CoV-2 who already have cross-reactive CD4⁺ memory T cells, compared to infected people without such memory:

• short asymptomatic infection;
• low SARS-CoV-2 viral load with a rapid reduction to undetectable levels within a few days;
• there may be a decrease in the generation of immune memory about SARS-CoV-2 due to a limited antigenic load.

Epidemiological consequences

Results for a population with a large number of people with pre-existing cross-reactive CD4⁺ memory T cells, compared to a community with fewer people with such memory:

• fewer hospitalizations and deaths due to reduced symptoms;
• potentially significantly lower spread rate due to lower viral load and shorter duration of virus isolation. It will presumably lessen the main reproductive number R⁰;
• the heterogeneity of contagion will increase even more than in scenario 2.

4. Transient infection

Lightning-fast activation of T_RM-cell immunity in the upper respiratory tract is unlikely and is an extreme variant of scenario 3. “Sterilizing immunity” is created by antibodies that prevent any cell infection. T cells can only respond after the cells are infected. Therefore, a massive activation of T_RM cells in the tissue can affect close to sterilizing immunity, leading to the destruction of all infected cells within a day after the initial infection. Such T cell events have only been reported in the presence of large numbers of CD8+ T_RM cells in specific animal models. There is no example where this is observed for CD4⁺ T cells, and available data show that CD4⁺ T_RM cells can only blunt infection for several days. It is also consistent with the fact that CD8+ T cells recognize antigens present on almost any infected cell (class I MHC representation), whereas CD4⁺ T cells recognize antigens represented only by a subset of cells (class II MHC representation).

In the case of the intranasal SARS-CoV vaccine described in the previous scenario, CD4⁺ T_RM cells eliminated virus replication within ~5 days. This fact contradicts in scenario 4.

If the pre-existing CD4⁺ T_RM cell immunity were so extreme that it prevented significant replication of the virus, the antibody response to SARS-CoV-2 would not have occurred. Such extreme immunity will not be detected by virological or serological diagnostic tests and will not spread the virus. These people will be immune to infection and will not be registered as ill. But this seems inconsistent with research on human coronavirus infection. In studies of human disease and reinfection with experimental coronavirus, even with the same or closely related strains and the benefit of antibody-mediated immunity, reinfection has often been observed, although not necessarily symptomatic. That makes it unlikely that cross-reactive T cell memory alone can eliminate SARS-CoV-2 infection.

Epidemiological consequences

Results for a population with a large number of people with pre-existing cross-reactive CD4⁺ memory T cells, compared to a community with fewer people with such memory:

• the maximum proportion of those who can become infected will be lower;
• the threshold for herd immunity will be lower.

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In General, according to scenarios 1-3, the discovery of cross-reactive T cells should not significantly change the predictions of disease dynamics in populations or, in particular, the proportion of the people that will become infected before transmission decreases. In contrast, in scenario 4, the threshold for herd immunity will be lower than in current projections based on R⁰ estimates, and the assumption that all people are at the same risk of infection.

Suppose cross-reactive T cells do reduce the severity of COVID-19 or SARS-CoV-2 isolation. In that case, different geographical or demographic populations may differ in disease severity or infectivity because they have different degrees of prior exposure to coronaviruses and, therefore, different degrees of T cell-mediated cross-immunity. It would mean that R⁰ would be lower in populations with widespread cross-immunity. This fact shows that R⁰ is not a constant of nature but a function of both the virus and the people, and R⁰ needs to be evaluated locally to make reliable local predictions.

It is important to note that CD4⁺ T cell memory’s potential impact does not explain all the differences observed concerning the severity of COVID-19 disease in any model. Other factors, such as comorbidities, old age, gender, or the size of the naive T cell repertoire, play an essential role in the severity of COVID-19.

These scenarios are also relevant for other viral infections and situations. For example, for vaccine-generated immunity to SARS-CoV-2, in the absence of sterilizing immunity, cross-reactive T cell memory may provide partial protective immunity and may also exist in parallel with the immunity generated by the vaccine.

Infectious immunity as a policy

An infection-based approach to herd immunity has been proposed to slow the spread of SARS-CoV-2. This approach is that low-risk groups are allowed to become infected while isolating susceptible groups. However, this strategy is fraught with risk. For example, even with moderate mortality rates, a new pathogen will lead to significant mortality because most of the population will not be immune to the pathogen. It is not appropriate to isolate high-risk groups since infections initially transmitted in low-mortality groups can spread to high-mortality groups. Moreover, there is no example yet of a large-scale successful herd immunity strategy based on deliberate conditions.

At the beginning of the COVID-19 pandemic, when other European countries introduced self-isolation in late February and early March 2020, Sweden decided against self-isolation. Initially, some local authorities and journalists described this as a herd immunity strategy: Sweden will do everything possible to protect the most vulnerable, but otherwise strive to ensure that enough citizens are infected to achieve proper herd immunity based on infections. By the end of March 2020, Sweden had abandoned this strategy in favor of active measures. Most universities and secondary schools were closed, travel restrictions were imposed, work at home was encouraged, and events with more than 50 people were banned. It was reported that the virus prevalence in Stockholm (Sweden) not only did not reach the threshold of herd immunity but also amounted to less than 8% in April 2020, which is comparable to the indicators of other cities – for example, Geneva (Switzerland) and Barcelona (Spain).

The population of the United States is about 330 million people. The world health organization estimates that the infection mortality rate is 0.5%, and about 198 million people in the United States must be immune to reach the herd immunity threshold of about 60%. It will result in several hundred thousand additional deaths. If we assume that at the moment infected with less than 10% of the population and formed infection immunity lasts 2-3 years (time unknown), it began to combat the pandemic herd immunity through infection at this stage is unrealistic. SARS-CoV-2 vaccines will help reach the herd immunity threshold, but the vaccine’s effectiveness and vaccination coverage remain to be seen.

Conclusions

Herd immunity is an essential defense against disease outbreaks. Even small deviations from protective levels can lead to epidemics due to local concentrations of susceptible people, as has been the case with measles over the past few years. Herd immunity is successfully maintained through vaccination. Therefore, vaccines must be useful, and vaccination programs must be adequate to ensure that those who cannot be directly protected will still receive relative protection.

Sources

• Herd Immunity and Implications for SARS-CoV-2 Control
• Cross-reactive memory T cells and herd immunity to SARS-CoV-2

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