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About viruses and viral disease

immune memory

How vaccines work

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Vaccines work by educating the host’s immune system to recall the identity of a virus years after the initial encounter, a phenomenon called immune memory. Viral vaccines establish immunity and memory without the pathogenic consequences typical of a natural infection. The success of immunization in stimulating long-lived immune memory is among humanity’s greatest scientific and medical achievements.

Immune memory is maintained by dedicated T and B lymphocytes that remain after an infection has been resolved, and most activated immune cells have died. These memory cells can respond rapidly to a subsequent infection (Figure). Ideally, an effective and durable vaccine is one that induces and maintains significant numbers of memory cells. If the host is infected again with this same pathogen, the memory B and T cells initiate a response that rapidly controls the pathogen before disease develops. This paradigm is true for most human viruses for which vaccines exist, including measles, mumps, and varicella-zoster viruses and poliovirus. In some cases, antigenic variation, such as occurs with influenza virus, precludes complete protection by a memory immune response, necessitating re-vaccination.

Protection from Infection or Protection from Disease?

The memory response elicited by most human viral vaccines does not protect against reinfection, but rather against the development of disease. An individual may be exposed repeatedly to viruses and never be aware of it, because the memory response eliminates the virus before signs and symptoms develop. After vaccination with inactivated poliovirus vaccine, virus replication may take place in the intestine, but effectively blocks the development of poliomyelitis. On the other hand, the human papillomavirus vaccine is over 90% effective at blocking infection. Consequently the HPV vaccine induces sterilizing immunity.

Whether or not COVID-19 vaccines will block infection is unknown because it has not been adequately measured. The results of a few small studies suggest that some of the vaccines may prevent infection. However these studies are not conclusive because they are being done shortly after vaccination, when serum antibody levels are much higher than they will be in, say, 6 months. Only then will we have an accurate measure of how well vaccination blocks infection with SARS-CoV-2. I suspect that none of the COVID-19 vaccines will block infection, but will reduce virus reproduction sufficiently to impede transmission in the population.

Population-wide immunity (aka herd immunity)

To be effective, a vaccine must induce protective immunity in a significant fraction of the population. Not every individual in the population need be immunized to stop viral spread, but the number must be sufficiently high to impede virus transmission. Person-to-person transmission stops when the probability of infection drops below a critical threshold. This effect is called herd immunity.

The herd immunity threshold is calculated as 1- 1/R0. R0 is the number of nonimmune individuals that on average will be infected upon encounter with an actively infected individual. As the reproduction number, R0, increases the value of 1/R0 decreases, and thus 1 − 1/R0 gets closer to 1, or 100%. For smallpox virus, the herd immunity threshold is 80 to 85%, while for measles virus (which has a high R0), it is 93 to 95%. Early in the COVID-19 outbreak the R0 of SARS-CoV-2 was calculated to be 2-3, which would produce a herd immunity threshold of 50-70%.

Herd immunity only works when a vaccine either blocks infection, or sufficiently reduces virus reproduction in the host to impede person to person transmission. As stated above, I see no reason why COVID-19 vaccines will not sufficiently reduce transmission to enable herd immunity.

No vaccine is 100% effective at inducing immunity in a population. Consequently, the level of immunity is not equal to the number of people immunized. For example, when 80% of a population is immunized with measles vaccine, about 76% of the population is actually immune, well below the 93 to 95% required for herd immunity.

What about T cells?

For many virus infections, antibodies are crucial for preventing infection. However, resolution of infection often requires the action of cytotoxic T cells, which kill virus infected cells. For vaccines that do not induce sterilizing immunity, it is likely that T cells play a role in eliminating virus-infected cells and preventing the development of disease.

This division of labor has been largely ignored in the discussion of COVID-19 vaccines. Most of the dialog has concerned the induction of antibodies and their ability to neutralize virus infection. COVID-19 vaccines do induce virus-specific T cells and it is likely that these will clear infections that begin in vaccinated indivduals. It has been reported that amino acid changes in SARS-CoV-2 variants of concern do not affect T cell epitopes, and that T cell responses in individuals who have either recovered from infection or have been vaccinated are not affected by these changes. Therefore it seems likely that even if variants of concern are able to overcome to some degree previous antibody immunity, they will be cleared by T cell responses, avoiding severe disease and death. The results of the phase III trial of the J&J COVID-19 vaccine support this presumption.

TWiV 684: Persistence of SARS-CoV-2 immune memory

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Daniel Griffin provides a clinical report on COVID-19, and Shane Crotty explains a study of antibodies, B cells and T cells in patients which suggests that immunological memory to SARS-CoV-2 might be long-lived.

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TWiV 677: Does antibody really know what time it is?

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Daniel Griffin provides a clinical report on COVID-19, then we discuss rapid deployment of SARS-CoV-2 testing by research laboratories in San Francisco, longitudinal observation of antibodies to SARS-CoV-2 in patients, and listener questions on vaccines, loss of smell, face masks, and more.

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TWiV 657: Shane Crotty on SARS-CoV-2 immunity

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Immunologist Shane Crotty joins TWiV to discuss the antibody and T cell responses to infection with SARS-CoV-2, followed by answers to listener questions.

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Adaptive immune defenses: Antibodies

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With the looming prospect of mass immunization against influenza, it’s important to understand how vaccines work. To do this we must have a good understanding of adaptive immune defenses. Today we’ll begin a discussion of the humoral arm of the adaptive immune response – antibodies.

Antibodies are large proteins produced by vertebrates that play important roles in identifying and eliminating foreign objects. The basic structural unit is composed of two heavy chains and two light chains, as shown in this diagram.

antibody

Antibodies bind other molecules known as antigens. Binding occurs in a small region near the ends of the heavy and light chain called the hypervariable region (labeled only on one arm in the figure). As the name implies, this region is extremely variable, which is why vertebrates can produce millions of antibodies that can bind many different antigens. The part of the antigen that is recognized by the antibody is known as an epitope.

There are five classes of immunoglobulin—IgA, IgD, IgE, IgG, and IgM—defined by the amino acid sequence of the heavy chain. They have different roles in immune responses; IgG, IgA, and IgM are commonly produced after viral infection.

During the first encounter with a virus, a primary antibody response occurs. IgM antibody appears first, followed by IgA on mucosal surfaces or IgG in the serum. The IgG antibody is the major antibody of the response and is very stable, with a half-life of 7 to 21 days. When an infection occurs with the same or a similar virus, a rapid antibody response occurs that is called the secondary antibody response. The specificity and memory of the antibody response are illustrated in the following graph.

immune-memory

A typical adaptive antibody response is shown as the relative concentration of serum antibodies weeks after injection of an animal with antigen A or a mixture of antigens A and B. Maximal primary response to antigen A occurs in 3 to 4 weeks. When the animal is injected with a mixture of both antigens A and B at 7 weeks, the secondary response to antigen A is more rapid and stronger than the primary response, demonstrating immunological memory. As expected, the primary response to antigen B requires 3 – 4 weeks. Antibody levels (also called antibody titers) decline with time after each immunization, a property known as self-limitation or resolution.

Antibodies are critical for preventing many viral infections, and may also contribute to the resolution of infection. We’ll next explore how antibodies accomplish these diverse activities.

Adaptive immune defenses

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adaptive-immune-systemThe immune response to viral infection comprises innate and adaptive defenses. The innate response, which we have discussed previously, functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.

The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader. The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.

The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.

Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.

A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory. The first adaptive response against a virus – called the primary response – often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.

The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. A complete understanding of how viruses cause cause disease requires an appreciation of the adaptive immune response, a subject we’ll take on over the coming weeks.