virology blog

About viruses and viral disease

infection

Herd Immunity and this Pandemic

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by Gertrud U. Rey

Photo courtesy of Andrea Lightfoot photography

Herd immunity occurs when a large enough percentage of the population has acquired either natural or vaccine-induced immunity against an infectious disease, thereby indirectly protecting a minority of non-immune individuals who are dispersed throughout the population. During this pandemic, many prominent scientists have stated that it is impossible to achieve herd immunity in the context of COVID-19, leading some to conclude that a mass SARS-CoV-2 vaccination campaign would be pointless. However, this thinking is flawed, and I want to explain why.

Traditionally, herd immunity is thought to create a barrier for the transmission of infectious agents, resulting not only in prevention of disease, but also prevention of infection. This understanding was based on previous observations that vaccination against poliovirus, measles virus, and other pathogens led to drastic reductions in the incidence of disease burden. It is reasonable to assume that if there is no disease, there is probably also no virus; and hence no viral infection or transmission of virus. However, past vaccination campaigns were not followed up with regular testing programs, so we actually have no way of knowing whether vaccination prevented infection and transmission! Considering that the vast majority of poliovirus infections are asymptomatic, it is possible that some polio virus infections and transmission occurred even after vaccination, despite the fact that those infections did not lead to disease.

The widespread testing measures adopted during the present pandemic have revealed the approximate frequency of asymptomatic SARS-CoV-2 infections, giving us a clearer understanding of the difference and dynamics between disease and infection. The type of immunity that prevents both disease and infection is called sterilizing immunity, and it is mostly thought to be induced by neutralizing antibodies, which inactivate infectious agents before they have a chance to infect a cell, thereby directly neutralizing the biological effect of the agent. However, any immune activity that prevents replication of a pathogen directly or indirectly necessarily induces sterilizing immunity, including the activity of non-neutralizing antibodies, whose binding can trigger other immune functions that can also prevent infection and replication.

Do SARS-CoV-2 vaccines induce sterilizing immunity? The answer to this question is complicated. There are many studies showing that most people have high levels of antibodies in the months following vaccination, and this large proportion of circulating antibodies could likely sequester an incoming virus before it has a chance to enter cells, infect them, and replicate. In this sense, the SARS-CoV-2 vaccines do induce sterilizing immunity, but only within a certain time period after vaccination. As antibody levels contract over time (a normal process), they leave behind a baseline population of memory B cells that can quickly expand and mass-produce new antibodies upon a subsequent encounter with SARS-CoV-2. Likewise, memory T cells can quickly react to incoming virus and virus-triggered signals, and destroy infected cells. Therefore, it is likely that when circulating SARS-CoV-2-specific antibody levels decline months and years after vaccination, the collective activity of memory immune cells will protect one from disease, but probably not infection, meaning that the SARS-CoV-2 vaccines no longer induce sterilizing immunity at that time. In other words, vaccinated people could briefly replicate and transmit low levels of virus, at least until memory immune responses kick in, which then prevent illness and additional viral replication and spread.

The emergence of new variants that are not as well recognized by existing vaccine-induced antibodies may also allow for some increased viral transmission, thus slowing down the establishment of immunity in the population. However, immune responses are not binary, and even a low level immune response that doesn’t protect against infection and spread but prevents serious disease can play a critical role in slowing down the pandemic. Vaccination has historically been very effective at suppressing community outbreaks, despite the fact that most vaccines do not induce sterilizing immunity.

Vaccination or natural immunity do not have to prevent all infections, and immunity does not have to last a lifetime for a pandemic to end. Pediatrician and vaccinologist Paul Offit defines herd immunity as the point where the serious disease burden is reduced sufficiently so as to no longer overwhelm the healthcare system. It’s becoming pretty clear that the pandemic is slowing down in the US, especially in the context of severe disease, hospitalization, and death; and that this is likely due to increased SARS-CoV-2 immunity among US residents. It is therefore likely that reduced illness and a shortened period of transmission from immune individuals will also reduce the overall rate of community infection and transmission. And in the end, it doesn’t matter whether we call it herd immunity, community immunity or some other name; the pandemic will end because a majority of the population is no longer susceptible to severe COVID-19.

[Please check out my video Catch This Episode 29 for an explanation of sterilizing immunity.]

The Esperanza Patient

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by Gertrud U. Rey

There is still no real cure for HIV infection. Only two people have been intentionally and successfully cleared of the virus thus far – the Berlin patient and the London patient. However, both subjects needed dangerous stem cell transplants to replenish their blood stem cells that had been destroyed during chemotherapy regimens needed to treat their HIV-induced blood cancers. In their transplants, doctors used bone marrow cells from a donor who was homozygous for a mutation in the gene encoding the HIV co-receptor CCR5 (CCR5 Δ32/Δ32), because this genotype confers resistance to HIV-1 infection. Such a transplant strategy cannot be realistically applied to most HIV patients.

Recently, a thirty-year-old female resident of Esperanza, Argentina, was declared to be cured of HIV-1 without receiving long-term treatment. The “Esperanza patient” is actually the second individual known to have cleared the infection naturally. The first person, known as the “San Francisco patient,” is a 67-year-old woman who appears to have cleared the virus in the absence of treatment after living with HIV for 28 years. Standard HIV treatment involves a combination of drugs known as antiretroviral therapy (ART), which is very effective at reducing the viral load in the blood of infected individuals and preventing transmission to others. However, ART does not eliminate all infected cells, allowing the persistence of a small pool of cells collectively known as the HIV reservoir. If ART is interrupted or terminated, the virus will begin replicating again within a couple of weeks because of this reservoir. The reservoir cells are capable of clonally expanding, and surprisingly, not all offspring of a clone exhibit identical levels of viral expression. Developing effective strategies to identify and eliminate such pools of cells is a prevailing challenge in the HIV field. Even the small group of HIV-infected individuals known as “elite controllers” who are able to maintain suppressed viral levels without ART retain a low frequency of intact integrated HIV DNA copies known as proviruses in their peripheral T helper cells.

The Esperanza patient was determined to be an elite controller because she had a very low viral load and no clinical or laboratory signs of HIV-1-associated disease for the entire eight years following her diagnosis, despite receiving no ART during that time. She only underwent ART when she became pregnant, but discontinued treatment after giving birth. To determine whether she had a persistent HIV-1 reservoir, the authors of a recent publication collected blood samples and placental tissue from the patient. They then isolated ~1.2 billion peripheral blood cells and ~0.5 million placental cells from the samples and subjected the cells to amplification and sequencing using primers and probes specific for HIV-1 in a technique that detects single, near full-length HIV-1 proviral genomes. The authors only detected seven proviral HIV-1 DNA species in the blood cells and none in the placenta. However, each of the seven HIV-1 DNA species was defective: one near-full-length sequence contained mutations that were lethal for the virus, and the other six sequences each contained large deletions. Three of these six sequences with deletions were completely identical to each other, suggesting that they were products of clonal expansion. These results distinguished the patient from other elite controllers, indicating that even though she had been infected with HIV-1 at some point and viral replication had occurred in the past, all viral DNA resulting from recent replication cycles was damaged.

The patient’s peripheral blood cells were also used to isolate 150 million T helper cells, which are the primary target of HIV-1. When the authors analyzed these T cells for the presence of replication-competent HIV-1 particles, they did not detect a single virion, a feature that further distinguished the Esperanza patient from other elite controllers, whose blood typically contains up to 50 replication-competent virions per milliliter.

The entry of HIV-1 into cells requires the presence of two cell surface proteins: the receptor CD4, and one of two co-receptors, either CXCR4 or CCR5. Individuals with a CCR5 Δ32/Δ32 genotype, which signifies a mutation in both copies of the gene encoding CCR5, are resistant to HIV-1 infection. Analysis of T helper cells isolated from the Esperanza patient revealed that they fully expressed both wild-type versions of CCR5 and CXCR4 co-receptors, and when tested in vitro, these cells were able to support HIV-1 infection and replication. This observation suggests that the patient was not resistant to infection. However, her serum did not contain the entire antibody profile usually found in HIV-1-positive patients, implying that even though she became infected and replicated virus, she never developed a full HIV-1-specific antibody response. 

The complete elimination of all virus-carrying cells in the context of HIV infection is termed a “sterilizing cure,” and the mechanism responsible for this exceedingly rare phenomenon is unclear. The human immune proteins APOBEC3G and APOBEC3F are known to induce destructive nucleotide changes in the HIV genome, and the authors hypothesize that the lethal mutations found in the near full-length HIV-1 proviral sequence were likely induced by these immune proteins. However, it is unclear why the overall number of proviral species was so low.

Whether or not the Esperanza patient will remain permanently free of HIV is currently unclear. The authors are careful to note that “absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses.” Nevertheless, this study suggests that a sterilizing cure of HIV-1 infection is possible, even if it is rare. The authors hope that additional data collected from the San Francisco and Esperanza patients will provide further insight into the mechanism responsible for a sterilizing cure, which might lead to treatments that cause the immune system to mimic the responses observed in these two patients.

[This article was written in honor of World AIDS Day, which occurs annually on December 1.]

Early Immune Responses to Herpes Simplex Virus Type I Infection

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by Gertrud U. Rey

Herpes simplex viruses infect cells of the skin and mucous membranes, where they establish a lifelong persistent infection in sensory neurons. Sporadic reactivation and viral shedding may lead to painful oral and genital disease and a three to five-fold increased risk of HIV transmission. There is currently no vaccine to prevent infection with herpes simplex virus type 1 or type 2 (HSV-1 or HSV-2).

Until recently it was thought that initial interactions of HSV-1 with the immune system only involve Langerhans cells. Langerhans cells are skin-resident sentinel macrophages that detect microbial antigens, and they engulf, process, and present these antigens to T cells for downstream immune functions. However, a recent study suggests that early during infection, HSV-1 also interacts with a newly identified immune cell known as an epidermal conventional dendritic cell type 2 (Epi-cDC2). Like Langerhans cells, dendritic cells can swallow microbe-infected cells and present the microbial antigens to T helper cells, ultimately triggering the actions of cytotoxic T cells, which directly kill infected cells.

The study aimed to better define the role of Epi-cDC2s in early HSV-1 infection using ex vivo explants as a model system. The explants consisted of pieces of human inner foreskin that were mounted on specialized gelatin scaffolds to mimic the in vivo environment encountered by HSV-1 during infection. The authors exposed the explants to an HSV-1 virus in which a viral membrane protein was fused to a green fluorescent protein (GFP), allowing them to visually track a resulting infection using a fluorescence microscope. This method revealed that at 24 hours after exposure to the GFP-tagged HSV-1, both Langerhans cells and Epi-cDC2s contained the virus in their cytoplasm, suggesting that these cells either engulfed HSV-1-infected skin cells and/or were themselves infected by HSV-1.

To determine whether the presence of HSV-1 in the cytoplasm of Epi-cDC2s resulted from infection and replication and not just from engulfing infected skin cells, the authors first did the following. They exposed cell cultures of Epi-cDC2s to HSV-1. After six hours of this exposure, Epi-cDC2s contained about as much virus as did control Langerhans cells, which are known to be infected by HSV-1. However, at 18 hours, Epi-cDC2s contained significantly higher HSV-1 levels than Langerhans cells, suggesting increased entry/uptake of virus into Epi-cDC2s compared to Langerhans cells. Next, to assess whether HSV-1 was also replicating in the Epi-cDC2 cells, not just entering them, the authors treated the cells with a fluorescent antibody that binds ICP27, a viral protein needed for replication. A significantly greater portion of Epi-cDC2s than Langerhans cells expressed ICP27, suggesting that HSV-1 was replicating, and doing so more efficiently in Epi-cDC2s.

Viruses may enter a host cell by a variety of mechanisms. One common mechanism, called receptor-mediated endocytosis, involves the formation of cell membrane-derived vesicles. In one version of this process, which requires a low pH, viral binding to a cell surface receptor triggers the cellular membrane to fold inward and form a slightly acidic “endosome” around the virus. Another version of receptor-mediated endocytosis is not dependent on a low pH, but requires cholesterol molecules and the motor protein actin to form cell surface protrusions called “ruffles.” When the ruffles become large enough, they collapse back onto the membrane and form large fluid-filled vesicles encasing the virus. In both of these versions of receptor-mediated endocytosis, the resulting vesicles enter the cytoplasm, where they eventually release their contents. In yet another mechanism of entry, also independent of acidic pH, viruses may simply fuse with the plasma membrane and deliver their contents into the cytoplasm.

Although HSV-1 can enter cells by any of these pathways, its entry mechanism differs in different types of cells. To determine which pathway HSV-1 uses to enter Langerhans cells and Epi-cDC2s, the authors treated both types of cells with a drug that prevents acidification of endosomes. They then infected the cells with the GFP-tagged HSV-1 and measured infection by quantitating GFP with a fluorescence microscope. Increasing doses of the drug led to increased inhibition of infection of Langerhans cells, suggesting that these cells are infected with HSV-1 via a pH-dependent mechanism. In contrast, the drug did not affect infection of Epi-cDC2s, suggesting that HSV-1 does not require an acidic pH for entering Epi-cDC2s.

To determine whether HSV-1 entry into Epi-cDC2s occurred via actin and cholesterol-dependent endocytosis, the authors treated Epi-cDC2s with inhibitors of actin or cholesterol prior to infection. Both treatments led to significant reduction in GFP fluorescence inside the cells, suggesting that cholesterol and actin are both important mediators of HSV-1 entry into Epi-cDC2s.

Langerhans cells express a cell surface receptor called langerin, which mediates entry of HIV and influenza A. To see whether this receptor is also required for entry of HSV-1, the authors infected Langerhans cells with HSV-1 in the presence of an antibody that neutralizes langerin. This inhibition of langerin expression led to diminished infection of Langerhans cells, suggesting that langerin is required for HSV-1 entry into them. In contrast, inhibition of langerin on Epi-cDC2s had no effect on HSV-1 infection efficiency, suggesting that, even though Epi-cDC2s do express some langerin, this receptor is not required for HSV-1 entry of these cells.

HSV-1 and HSV-2 are of high public health concern, and a vaccine to prevent infection with these viruses is urgently needed. Immune control of HSV-1/-2 infection and resolution of genital herpes lesions requires the collective action of various types of T cells, which are likely primed by different dendritic cell subsets. Understanding the dynamics of the initial interactions of HSV-1 and HSV-2 with cells of the immune system may result in better strategies for HSV-1/-2 vaccines. The pathways described here have important implications in vaccine design and prevention of persistent infection of neuronal cells.

The Route Matters

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by Gertrud U. Rey

There are currently 315 therapeutic drugs and 210 vaccine candidates in development to treat or prevent SARS-CoV-2 infection. Many of these vaccines are designed to be administered by injection into the muscle. 

Intramuscular injection of a vaccine antigen typically induces a systemic (serum) immune response that involves the action of IgM and IgG antibodies. IgM antibodies appear first and typically bind very strongly to antigens, to the extent that they often cross-react with other, non-specific antigens. IgG antibodies arise later, are a lot more specific than IgM, and provide the majority of antibody-based immunity against invading pathogens. Intramuscular immunization usually does not induce very high levels of serum IgA, a type of antibody that is more prevalent in mucosal surfaces and represents a first line of defense against invasion by inhaled and ingested pathogens. The role of IgA in the serum is mostly secondary to IgG, in that IgA mediates elimination of pathogens that have breached the mucosal surface.    

Several of the SARS-CoV-2 vaccine candidates currently in clinical trials consist of a replication-deficient adenovirus with an inserted gene that encodes a SARS-CoV-2 antigen. The suitability of adenoviruses as vectors for delivering foreign genes into cells was discussed in a previous post, which summarized preliminary phase I/II clinical trials assessing the safety and efficacy of a chimpanzee adenovirus-vectored replication-deficient SARS-CoV-2 vaccine candidate encoding the full-length SARS-CoV-2 spike protein (AZD1222). The spike protein has been the primary antigenic choice for a number of SARS-CoV-2 vaccine candidates because it mediates binding of the virus to the ACE2 host cell receptor via its receptor-binding domain (RBD), and it also mediates fusion of the viral particle with the host cell membrane via its fusion domain. Both of these spike domains are highly immunogenic and are targeted by neutralizing antibodies, which bind viral antigens, inactivating virus and preventing infection of new cells. However, preliminary results suggest that AZD1222 only protects against SARS-CoV-2 lung infection and pneumonia but doesn’t appear to prevent upper respiratory tract infection and viral shedding.

To mediate fusion of the virus particle to the host cell membrane, the SARS-CoV-2 spike protein undergoes a structural rearrangement from its pre-fusion conformation. Because the pre-fusion form is more immunogenic, vaccines encoding the spike protein often contain a mutation that locks the translated spike protein into this pre-fusion structure. In a recent publication, virologist Michael Diamond and colleagues analyzed the efficacy of an adenovirus-vectored SARS-CoV-2 vaccine candidate and compared its protective effects after intramuscular injection to those after administration by the intranasal route. The vaccine, named ChAd-SARS-CoV-2-S, is similar to AZD1222 except that its spike gene encodes the pre-fusion stabilized spike protein. To assess the antibody responses induced by intramuscular vaccination with ChAd-SARS-CoV-2-S, the authors injected mice with 10 billion viral particles of either ChAd-SARS-CoV-2-S or a control vaccine consisting of the same adenovirus shell, but lacking the spike protein gene insert. They found that one dose of ChAd-SARS-CoV-2-S induced strong serum IgG responses against both the entire spike protein and the RBD, but no IgA responses in the serum or in mucosal lung cells.

While antibodies are an important part of the adaptive immune response, cell-mediated immunity is just as important and at the very least results in activation of white blood cells that destroy ingested microbes and also produces cytotoxic T cells that directly kill infected target cells. During a first exposure to a pathogen, T helper cells typically sense the presence of antigens on the surface of the invading pathogen and release a variety of signals that ultimately stimulate B cells to secrete antibodies to those antigens and also stimulate cytotoxic T cells to kill infected target cells. Analysis of these T cells in mice immunized with one or two doses of intramuscularly administered ChAd-SARS-CoV-2-S revealed that two vaccine doses induced both T helper and cytotoxic T cell responses against the whole spike protein. Collectively, these results suggest that although intramuscular vaccination produces strong systemic adaptive immune responses against SARS-CoV-2, it induces little, if any, mucosal immunity.

To determine whether intramuscular immunization with ChAd-SARS-CoV-2-S protects mice from infection, the authors intentionally infected (“challenged”) immunized mice with SARS-CoV-2. Although a single vaccine dose protected the mice from SARS-CoV-2 infection and lung inflammation, the mice still had high levels of viral RNA in the lung after infection, suggesting that intramuscular administration of the vaccine does not lead to complete protection from infection.  

In an effort to see whether vaccination by the intranasal route provides more complete protection, the authors inoculated mice with a single dose of ChAd-SARS-CoV-2-S or control vaccine through the nose. Analysis of serum samples and mucosal lung cells four weeks after vaccination revealed that recipients of ChAd-SARS-CoV-2-S had high spike- and RBD-specific levels of neutralizing IgG and IgA in both the serum and the lung mucosa, and that the number of B cells producing IgA was about five-fold higher than that of B cells producing IgG. Interestingly, the neutralizing antibodies were also able to inactivate SARS-CoV-2 viruses containing a D614G change in the spike protein, suggesting that ChAd-SARS-CoV-2-S can effectively protect against other circulating SARS-CoV-2 viruses. Intranasal vaccination also induced SARS-CoV-2-specific cytotoxic T cells in the lung mucosa, specifically T cells that produce interferon gamma, an important activator of macrophages and inhibitor of viral replication.

The ideal immune response is “sterilizing” – meaning that it completely protects against a new infection and does not allow the virus to replicate at all. To evaluate the ability of a single intranasal dose of ChAd-SARS-CoV-2-S to induce sterilizing immunity, the authors analyzed immunized and infected mice for serum antibodies produced against the viral NP protein. Because the vaccine does not encode the NP protein, any antibodies produced against this protein would be induced by translation of the NP gene from the challenge virus and active replication of the virus. All of the mice immunized with a single dose of intranasally administered ChAd-SARS-CoV-2-S had very low levels of anti-NP antibodies compared to recipients of the control vaccine, suggesting that ChAd-SARS-CoV-2-S induced strong mucosal immunity that prevented SARS-CoV-2 infection in both the upper and lower respiratory tract. This means that if intranasally immunized mice were to be exposed to SARS-CoV-2, they would not be able to replicate the virus or transmit it to others. 

The study has some notable limitations. First, it is well known that mice can be poor predictors of human disease outcomes. Second, because the mouse ACE2 receptor doesn’t easily bind SARS-CoV-2, the mice were engineered to express the human ACE2 receptor, which added a further artificial variable to an already imperfect model system. Third, it is presently unknown how long the observed immune responses would last. That being said, studies with influenza virus have shown that mucosal immunization through the nose can elicit strong local protective IgA-mediated immune responses. Further, there are clear advantages to intranasal vaccine administration: inoculation is simple, painless, and does not require trained professionals. The adequacy of a single dose would also lead to more widespread compliance. Lastly, a vaccine that prevents viral shedding would be ideal, because in addition to preventing disease in the exposed individual, it would prevent transmission to others. 

None of the SARS-CoV-2 vaccine candidates currently in clinical trials are delivered by the intranasal route. If the results observed in these mouse experiments can be duplicated in humans, ChAd-SARS-CoV-2-S would clearly be superior to other SARS-CoV-2 vaccine candidates. 

Your viral past

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virusesDid you ever wonder what different virus infections you have had in your lifetime? Now you can find out with just a drop of your blood and about $25.

Immune defense systems of many hosts produce antibodies in response to virus infections. These large proteins, which are generally virus specific, can block or inhibit virus infection, and persist at low levels for many years after the initial infection. Hence it is possible to determine whether an individual has had a virus infection by looking for anti-viral antibodies in the blood. Up to now the process of identifying such antibodies has been slow and limited to one or a few viruses. A new assay called VirScan allows unbiased searches for all the virus antibodies in your blood, providing a picture of all your past infections.

To identify the human antivirome, DNAs were synthesized encoding proteins from all viruses known to infect humans – 206 species and over 1000 strains. These DNAs were inserted into the genome of a bacteriophage, so that upon infecting bacteria, the viral peptides are displayed on the phage capsid. These ‘display’ phages were then mixed with human serum, and those that were bound by antibodies were isolated. The DNA sequence of the phage genomes were then determined to identify the human virus bound by the antibodies.

This method was used to assay samples from 569 humans. The results show that each person had been exposed to an average of 10 viruses, with a range from a few to over 20 (two individuals had antibodies to 84 different virus species!). The most frequently identified viruses included herpesviruses, rhinoviruses, adenoviruses, influenza viruses, respiratory syncytial virus, and enteroviruses. The overall winner, found in 88% of samples, is Epstein-Barr virus.

These results are not unexpected: all of us are infected with at least a dozen viruses at any time, and the viruses identified in this study known to infect much of the human population. What was surprising is the absence of some common viruses, such as rotaviruses, and the ubiquitous polyomaviruses. According to serological surveys, the most common human viruses are the small, single-stranded DNA containing anelloviruses. Yet the related torque teno virus was only found in 1.7% of samples. These differences are likely due to a combination of technical and biological issues (e.g., failure of antibodies to certain viruses to persist in serum).

This new assay may one day become a routine diagnostic tool that is used along with complete blood counts and chemistries to know if a patient’s signs and symptoms might be attributable to a past virus infection. VirScan technology is not limited to virus infections – it can be used to provide a history of bouts with bacteria, fungi, and parasites.

VirScan might also allow us to determine which virus infections are beneficial, and which contribute to chronic diseases such as autoimmune or neurodevelopmental disorders or cancer. The assay can be used to conduct unbiased population-based studies of the prevalence of virus infections and their possible association with these diseases. Such connections were not previously possible with antibody assays that search for one virus at a time. This approach was not only inefficient, but required guessing the responsible virus.

Some other findings of this study are noteworthy. As expected, children had fewer virus infections than adults. HIV-positive individuals had antibodies to more viruses than HIV-negative individuals, also expected given the damage done by this virus to the immune system. Frequencies of anti-viral antibodies were higher outside of the United States, possible due to differences in genetics, sanitation, or population density. In most samples, there was a single dominant peptide per virus, although there were occasional differences among populations. This information might be useful for improving vaccines, or tailoring them to specific countries or regions.

Update: It would be very informative to use VirScan to search for antibodies against viruses that are not known to infect humans. Other animal viruses, plant viruses, insect viruses: to which do a significant fraction of humans respond? The information might identify other viruses that replicate in humans and which might constitute future threats (or present benefits).

The incubation period of a viral infection

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Incubation periodThe time before the symptoms of a viral infection appear is called the incubation period. During this time, viral genomes are replicating and the host is responding, producing cytokines such as interferon that can have global effects, leading to the classical symptoms of an acute infection (e.g., fever, malaise, aches, pains, and nausea). These symptoms are called the prodrome, to distinguish them from those characteristic of infection (e.g. paralysis for poliovirus, hemorrhagic fever for Ebolaviruses, rash for measles virus).

Whether or not an infected person is contagious (i.e. is shedding virus) during the incubation period depends on the virus. For example, Ebola virus infected patients do not pass the virus on to others during the incubation period. This fact explains why Tom Frieden said there was ‘zero chance’ that the passenger from Liberia who was diagnosed with Ebola virus infection in Dallas would have infected others while on an airplane. He had no symptoms of infection because he was still in the incubation period of the disease.

In contrast to Ebolaviruses, poliovirus and norovirus are shed during the incubation period – in the feces, where they can infect others.

Remarkably, viral incubation periods can vary from 1 or 2 days to years (Table; click to magnify). Short incubation times usually indicate that actions at the primary site of infection produce the characteristic symptoms of the disease. Longer incubation times indicate that the host response, or the tissue damage required to reveal the symptoms of infection, take place away from the primary site of infection.

The table was taken from the third edition of Principles of Virology. Missing from the table (which will be corrected in the next edition) is the incubation period of Ebola virus, which is 2 to 21 days. I would also argue that the incubation period of HIV is not 1-10 years, but 2-4 weeks, the time until the prodromal symptoms occur. The characteristic symptom of HIV-1 infection, immunosuppression, occurs much later.