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About viruses and viral disease

ring vaccination

Should we be worried about monkeypox?

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by Gertrud U. Rey

The prevalence of monkeypox cases is continuing to increase around the world, with 7,243 total confirmed global cases as of today. Although this sounds awfully familiar, monkeypox virus is highly unlikely to cause a pandemic like the one we are presently experiencing, for at least two reasons: 1) monkeypox virus is not transmitted as easily as SARS-CoV-2, and 2) we have all the tools needed for quelling local outbreaks, thus hopefully preventing further community spread.

Because monkeypox has been endemic to Central and West Africa for several decades, scientists have had ample time to develop a thorough understanding of the virus and its associated disease. Monkeypox virus belongs to the Poxviridae, a family of viruses that also includes cowpox virus, variola virus (which causes smallpox), and vaccinia virus (the source of the modern smallpox vaccine). The name “monkeypox” resulted from the fact that the virus infects primates and was initially isolated from a laboratory monkey. However, it is actually thought to also circulate in rodents, which occasionally come into contact with humans, who can then further spread it to other humans.

Human-to-human transmission of monkeypox virus is far less efficient than that of SARS-CoV-2, which is commonly spread in the absence of symptoms, whereas monkeypox virus is only thought to be transmitted while an infected person is symptomatic. In addition, SARS-CoV-2 is readily spread when an infected person breathes, sneezes, or coughs around other people. In contrast, monkeypox virus is only transmitted by direct contact with lesion material or inhalation of respiratory droplets during prolonged face-to-face interaction with an infected person. Recent news reports have highlighted clusters of infections among men who have sex with men, leading some to infer that monkeypox is a sexually-transmitted disease. However, there is no evidence to suggest that the virus is present in sexual bodily fluids, therefore, it is not considered to be a sexually-transmitted pathogen. The high incidence of infections in the gay community could be explained by transmission through very close contact, which, by definition, includes sex.

The incubation period for monkeypox virus can range from 5 to 21 days, with an average of one week between infection and onset of symptoms. Initial symptoms usually include fever, swollen lymph nodes, headache, and muscle aches; and these symptoms are followed by a distinctive skin rash consisting of clear fluid-filled vesicles. The vesicles eventually fill with pus and ultimately crust over to give way to a new layer of healthy skin. Early symptoms are similar to those of chickenpox, which is caused by varicella-zoster virus (a herpesvirus, unrelated to poxviruses). However, unlike chickenpox lesions, which can individually exist in different stages of development throughout the course of infection, monkeypox lesions typically appear, progress, and disappear together.

Should the need arise, there are at least two licensed smallpox-specific vaccines that can also prevent monkeypox. ACAM2000 is a replication-competent live-attenuated vaccinia virus developed by Sanofi Pasteur Biologics Co. This vaccine is administered with a traditional bifurcated needle, and although very effective, it is associated with pretty severe side effects, including sore arm, fever, body aches, and occasional myocarditis. MVA-BN (marketed as “Jynneos” in the US) is a highly attenuated replication-incompetent vaccinia virus produced by Bavarian Nordic. MVA-BN/Jynneos is delivered by injection under the skin, is much better tolerated than ACAM2000, and is approved to be used as a monkeypox-specific vaccine. Fortunately, because of the long incubation period, it is possible to be vaccinated shortly after an exposure to monkeypox virus and still be protected from monkeypox disease.

It is unclear how long either of the available vaccines protect a person from disease, and whether individuals who were immunized against smallpox decades ago are protected from monkeypox today. Routine global smallpox vaccination ended in the late 1970s, so it is likely that the current outbreaks are fueled by non-immune people who were born since then, and/or by vaccinated individuals whose immunity has waned. However, even if infections continue to increase in number, it is unlikely that everybody in the general population would need to be vaccinated. Instead, proactively administering the vaccine to contacts and contacts of contacts of an infected person in a strategy termed “ring vaccination” would probably be sufficient to stop spread. That is, the vaccine would be administered in an area in a ring around the outbreak.

There are also several FDA-approved antiviral drugs that could be effective against monkeypox virus infection. Tecovirimat, which can be taken orally, prevents release of newly formed viral particles from infected cells, thus potentially blocking transmission of monkeypox virus. Cidofovir (administered by infusion into the vein) and its derivative brincidofovir (taken orally), disrupt replication of smallpox virus and could thus also be used for treating monkeypox virus infection.  

Considering all these factors, the average person is at low risk of becoming infected with monkeypox virus. Nevertheless, the World Health Organization has declared that there is no room for complacency and is urging governments to take some coordinated action to stop the spread of the virus. Because we have the tools to deal with monkeypox outbreaks and have hopefully learned from the disorganized manner in which the present pandemic was handled initially, a federal preparedness response should be implemented as soon as possible.

[The monkeypox outbreak was previously covered at least on Infectious Disease Puscast episodes 3 and 4; TWiV 902, TWiV 915; and TWiV Special Monkeypox Clinical Update with Dr. Daniel Griffin.]

TWiV 349: One ring to vaccinate them all

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On episode #349 of the science show This Week in Virology, Vincent, Alan and Rich explain how to make a functional ribosome with tethered subunits, and review the results of a phase III VSV-vectored Ebolavirus vaccine trial in Guinea.

You can find TWiV #349 at www.microbe.tv/twiv.

An Ebolavirus vaccine in Africa

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filovirionAn Ebolavirus vaccine has shown promising results in a clinical trial in Guinea. This vaccine has been in development since 2004 and was made possible by advances in basic virology of the past 40 years.

The ability to produce the Ebolavirus vaccine, called rVSV-EBOV, originates in the 1970s with the discovery of the enzyme reverse transcriptase, the development of recombinant DNA technology, and the ability to rapidly and accurately determine the sequence of nucleic acids. These advances came together in 1981 when it was shown that cloned DNA copies of RNA viral genomes (a bacteriophage, a retrovirus, and poliovirus), carried in a bacterial plasmid, were infectious when introduced into mammalian cells. Production of an infectious DNA copy of the genome of vesicular stomatitis virus (VSV) was reported in 1995. In their paper the authors noted:

Because VSV can be grown to very high titers and in large quantities with relative ease, it may be possible to genetically engineer recombinant VSVs displaying foreign antigens. Such modified viruses could be useful as vaccines conferring protection against other viruses.

This technology was subsequently used in 2004 to produce replication competent VSV carrying the genes encoding the glycoproteins of filoviruses, which others had shown are the targets of neutralizing antibodies. When injected into mice, these recombinant viruses induced neutralizing antibodies that were protective against lethal disease after challenge with Ebolavirus.

In a series of experiments done over the next 10 years, rVSV-EBOV was shown to protect nonhuman primates from lethal disease. In these experiments, animals were injected intramuscularly with the vaccine and challenged with Ebolavirus. The vaccine induced protection against lethal disease and prevented viremia. Extensive studies of the VSV vector in ~80 nonhuman primates showed no serious side effects, and only transient vector viremia.

The rVSV-EBOV was originally developed by Public Health Agency of Canada, and subsequently licensed to NewLink Genetics. Financial support has been provided from Canadian and US governments and others. From 2005 to the present, the NIH Rocky Mountain Laboratory in Hamilton, Montana has also been involved in this work, particularly with nohuman primate challenge studies. In November 2014 Merck entered an agreement with NewLink to manufacture and distribute the vaccine.

In August 2014, well into West Africa Ebolavirus outbreak, Canada donated 800 vials of vaccine to WHO, which then established the VSV Ebola Consortium (VEBCON) to conduct human trials.

The results of Phase I trials of rVSV-EBOV in Africa (Gabon, Kenya) and Europe (Hamburg, Geneva) were published on 1 April 2015. These trials comprised three open-label, dose-escalation trials, and one randomized, double blind controlled trial in 158 adults. Each volunteer was given one injection of 300,000 to 50 million plaque-forming units of rVSV-EBOV or placebo. No serious vaccine related events were reported, but immunization was accompanied by fever, joint pain, and some vesicular dermatitis. A transient systemic infection was observed, followed by development of Ebolavirus-specific antibody responses in all participants, and neutralizing antibodies in most.

The interim results of a phase III trial of rVSV-EBOV, begun on 23 March 2015 in Guinea, have just been published. It is a cluster-randomized trial with a novel design that is modeled on the ring vaccination approach used for smallpox eradication in the 1970s. In ring vaccination, individuals in the area of an outbreak are immunized, in contrast to treating a larger segment of the population. During this trial, when a case of Ebolavirus infection was identified, all contacts and contacts-of-contacts were identified. Some of these individuals were immediately immunized intramuscularly with 2 x 107 PFU, and others (randomly chosen) were immunized three weeks later. The primary outcome was Ebolavirus disease confirmed by PCR. As new cases arose in other areas (clusters), these were treated in the same way, hence the name of cluster-randomized trial.

The press has widely reported that the vaccine was ‘100% protective’. This outcome sounds much better than is represented by the data, so let’s look at the numbers.

Zero cases of Ebolavirus disease were observed in 2,014 immediately vaccinated people, while 16 cases were identified in those given delayed vaccine (n=2,380). These numbers were used to calculate the vaccine efficacy of 100%. While statistically significant, the numbers are small.

More telling are the results obtained when we consider all individuals eligible for immunization, not just those who were immunized (some were excluded for a variety of reasons). Of 4,123 eligible individuals, 2,014 were immunized as noted above, but 2,109 did not receive vaccine. Eight cases of Ebola virus disease were noted in the non-immunized population. This number is small, a consequence of the fact that the outbreak is waning.

On the basis of these interim results, the data and safety monitoring board decided that the trial should continue. However because the board felt that the vaccine is a success, they decided to curtail randomization of subjects into immediately vaccinated and delayed vaccinated groups. Now all contacts and contacts-of-contacts will immediately receive vaccine. As a consequence of this change, it will not be possible to improve the accuracy of vaccine efficacy. For example, when many more individuals are immunized in the future, many fewer that 100% might be protected from disease.

There are two lessons I would like you to remember from this brief history of an Ebolavirus vaccine. Developing a vaccine takes a long time (minimum 11 years for rVSV-EBOV) and depends on advances made with both basic and clinical research.  Don’t believe anyone who says that this vaccine was made in a year. And always look at the numbers when you hear that a vaccine has 100% efficacy.