As of today, 20 July, the number of confirmed cases of monkeypox globally, according to the US Centers for Disease Control (CDC) is 14,268, with a large increase in the US to 2107 cases. Spain remains the country with the highest number of cases both absolutely and per head, with 3125 now confirmed, the UK with 2137, and Germany 2033. The next highest number of cases belongs to France, with just under 1000.
Who’s getting monkeypox
Analyses of cases are being reported to TESSy, the European Surveillance System database, which covers the whole World Health Organization (WHO) Europe region. The following figures use different samples of cases and none are of all cases, but give a guide to the frequency of different characteristics and outcomes.
Perhaps most importantly: out of 3506 resolved (i.e. not ongoing) cases so far, there have been no deaths. Life-threatening illness also seems rare: among a sample of 841 patients, only three (0.4%) were admitted to intensive care units.
However currently over 10% are being hospitalised, putting further strains on systems already coping with the summer heatwave and an upsurge in COVID. (France and Italy have seen particularly big increases in COVID cases in the last month).
Out of a sample of 1788 patients, 183 (10.2%) were hospitalised. Of these, 16% were admitted purely for isolation and observation but 53% (5.5% of all cases) were admitted due to clinical symptoms such as acute throat and rectal pain, difficulty swallowing and bacterial infections of lesions.
The vast majority of cases have been in men – only 0.4% or 21 cases out of all 6892 reported up to 5 July was female, and two of those were in the four cases seen in children under 18.
There continues to be a strong association between monkeypox and HIV, with 561 (43%) out of a sample of 1313 cases being people living with HIV.
Reporting to TESSy of sexual orientation is inconsistent but it is still assumed that most infections are in gay men. Two to three per cent of cases are in health workers, but they did not all necessarily acquire monkeypox at work.
The monkeypox vaccine
Apart from a few existing stocks of the second-generation ACAM2000 vaccine that uses a live attenuated virus, the vaccine used is MVA-BN. This uses a cowpox virus – MVA or modified vaccinia Ankara – that is so highly attenuated it may effectively be regarded as a killed virus.
The vaccine’s efficacy is consistently cited by bodies such as the WHO as 85%, in other words preventing 17 out of every 20 infections. But as the US CDC makes clear, the only efficacy data was from animal studies conducted in Africa in the 1980s, and human efficacy was extrapolated from this when the same immune responses were observed in humans.
MVA is used as a vaccine in its own right and also as a delivery vector for other vaccines, including experimental HIV vaccines. It introduces viral proteins to the B-cells and T-cells of the immune system and stimulates an immune response. However, it lacks the genes that enable it to produce more viral particles – and the genes that can get round the immune mechanisms that stop it mutating so it can replicate.
It is injected subcutaneously into the upper arm but does not produce the lesion old-fashioned smallpox vaccines did, and also produces fewer flu-like symptoms and other systemic side effects.
Although the vaccine was developed by the European firm Bavarian Nordic (hence ‘MVA-BN’), it is only licensed for use against monkeypox in the US (under the brand name Jynneos) and in Canada (as Imvamune). In Europe, where it has the brand name Imvanex, it was only licensed by the European Medicines Agency (EMA) for smallpox and specifically not for use in under-16s. So any current use for monkeypox is ‘off-label’, meaning that it is being used for a different disease to the one it was licensed for. The EMA started a fast-track review with a view to extending its indication to monkeypox on 28 June.
Vaccine availability is still poor in Europe but on 18 July the Health Emergency preparedness and Response Authority (HERA) of the European Centre for Disease Control (ECDC) announced that it had secured another 54,530 doses to add to 109,090 already announced, totalling 163,620 doses. The UK Health Security Agency announced it had secured another 100,000 doses in addition to 30,000 already supplied in June.
‘Secured’ does not necessarily mean imported, let alone distributed to clinics. According to a French press report on Monday, the French Health Minister announced that 7,500 doses of the existing national stock of smallpox vaccines had already been made available to clinics, with 5000 more doses expected to arrive from HERA this week and the next.
Last Wednesday BASHH, the British Association for Sexual Health and HIV, announced that in response to escalating numbers of cases in London, additional vaccine would be supplied to the larger London sexual health clinics. Because of this, clinics operating outside London were not able to order more vaccine last Sunday when supplies would normally be released. BASHH said: “This is a temporary situation and it is hoped that out-of-London clinics will receive supplies soon.”
Meanwhile over the Atlantic, the US Federal Government made 56,000 doses of its Jynneos stockpile available to state health systems, and officials told Science on 1 July that they expected to receive an additional 296,000 doses from Bavarian Nordic “in the coming days.”
In the UK, a consensus statement released by a coalition of clinicians, public health bodies and community organisations forecast that almost this number of vaccine doses would be needed for the UK alone. They estimate that 250,000 doses of vaccine would have to be procured for 125,000 people. The 125,000 is a rough estimate made by adding the number of gay and bisexual men and trans women currently using or in need of PrEP, to the number who are HIV-positive and at similar risk of monkeypox.
Vaccine efficacy – one dose or two?
It’s possible we may not need so many doses, though. The UK consensus statement bases its estimate on 1980s data of the 85% efficacy of the previous MVA-based smallpox vaccination in combating the more virulent strain of monkeypox that is endemic to central Africa. It is clear that the current epidemic strain comes from the less virulent west African variant, though the speed with which it is mutating to spread untypically and with different presentation has the experts worried.
It is also based on the need for two vaccine shots given four weeks apart. But some studies have found the Jynneos produces as high a level of immunity within two weeks as ACAM2000 does within a month. The second shot’s main use is to prolong the duration of immunity, which may be less important when containing a fast-spreading epidemic situation in a sub-population.
In the current situation where the supply of vaccine for a previously rare tropical disease, made by a sole manufacturer, does not meet the surge in demand, some countries are already taking the pragmatic decision to vaccinate as many at-risk people as possible with one jab and wait till supplies are more secure to offer second doses.
For example, the UK’s ‘vaccines bible’ the Green Book says “The Joint Council for Vaccines and Immunisation has proposed that vaccination should be offered as soon as feasible to those… at highest risk of exposure. The initial priority is to deliver first doses to as many gay and bisexual men who have sex with men in the highest risk group as possible. Subject to the evolving epidemiology, a second dose may be advised around 2-3 months later to provide longer lasting protection.”
At present, in the US, the FDA is officially sticking to its two-jab guideline but France is reported also to be considering the pragmatic use of one jab or at least a longer wait till boosting.
In other words, wait and see. Given that older studies have found that immunity conferred by ACAM2000 and its predecessors appears to persist at useful levels for over two years, health authorities are clearly hoping that monkeypox may not be around long enough as an epidemic for re-vaccination to be needed.
On the other hand, studies using the ACAM2000 vaccine as post-exposure prophylaxis in healthcare workers exposed to smallpox suggested an efficacy of 45% for one shot – but noted some of these shots were given well over the limit of four days after exposure, within which PEP vaccination is most efficacious.
The exception to the one-dose strategy is severely immunocompromised people – who, the Green Book says, definitely need two shots. At present the Green Book does not stipulate what the definition of ‘severely immunocompromised’ means, which echoes the lack of clarity about who should receive COVID vaccine boosters. A clearly stated CD4 count threshold would be useful.
Vaccine strategy and modelling
One thing is clear: while isolation and contact tracing help, they are not going to be sufficient to contain monkeypox. In its first rapid risk assessment on the monkeypox outbreak, the ECDC stated that “Unless contact tracing can successfully identify a high proportion of infected contacts, mathematical modelling results indicate that targeted pre-exposure prophylaxis (PrEP) of individuals at high risk of exposure would be the most effective strategy to use vaccines to control the outbreak”. ‘PrEP’ here means using the monkeypox vaccine as prophylaxis against that disease, not using antiretrovirals to prevent HIV.
Although it is yet to be shown exactly how monkeypox is spread, and cases among healthcare workers and children show that it’s not always an STI, viral assays have shown that exposure during the kind of activities associated with sex – not just to body fluids but also to things like contaminated clothing – are the most likely sources of infection.
The virus has a relatively long incubation period of about three weeks before any symptoms start. Although it has now been established that people can have asymptomatic infections, it is still assumed that there is a lag between people being infected and becoming infectious – much longer than there is for diseases such as HIV and COVID.
This means, firstly, that isolation, contact tracing, quarantine of contacts, and post-exposure vaccination of contacts could work better than with COVID, for instance. This strategy is what eventually contained the Ebola outbreaks in Africa in 2014 and 2018. The technique of post-exposure vaccination of contacts (and of contacts of contacts) is called “ring vaccination”. This is still the strategy the World Health Organization recommends, though it is being rapidly overtaken by events.
The strategy works best in tightly knit communities where someone who develops the disease knows who they recently have been in contact with. It is less effective in situations like a modern urban gay scene where people may not be able to trace their contacts, especially of a disease whose exact mode of transmission is still unclear.
Modelling done by ECDC and HERA, presented at an ECDC call on 12 July, looked at six different strategies and their efficacy in bringing a modelled monkeypox outbreak under control within three months.
These six different strategies were:
- Isolation of cases
- Isolation of cases and quarantine of contacts (initial assumption was that 50% of known and 10% of unknown contacts would be traced)
- Isolation of cases, quarantine and post-exposure vaccination of contacts
- Isolation of cases, quarantine and post-exposure vaccination of contacts, post-exposure vaccination of their contacts (the Ebola strategy)
- Isolation of cases, quarantine and post-exposure vaccination of contacts, plus pre- exposure vaccination of highly at-risk target populations
- Isolation of cases, quarantine of contacts, pre- exposure vaccination of highly at-risk target populations only.
These were then tested under assumptions of either a 20% vaccination uptake rate or an 80% uptake rate.
The first finding was that isolation of cases, and tracing of and quarantine of contacts, were actually the major parts of what contained the outbreak with the three-month time horizon.
Just isolating cases led to a 45% likelihood of containing the outbreak, adding in contact tracing and quarantine of contacts took that likelihood to 60%, and expanding the reach of contact tracing, to 80% of known and 20% of unknown contacts traced, would take it to 65%.
The second finding is that post-exposure vaccination of contacts would add very little to isolation and quarantine tactics. Twenty per cent vaccine coverage would add nothing and 80% vaccine coverage would add only 5% to the probability of three-month containment, to 60%, unless contact tracing was more successful.
If contact tracing was more successful, post-exposure vaccination of contacts would push the three-month containment probability up to 70%, and 75% if the contacts of contacts were also vaccinated. But this is for a disease with less obvious and dramatic early symptoms than Ebola and which is spread more anonymously, so this might be hard to achieve.
Pre-exposure vaccination of targeted at-risk communities worked better. This involves offering the vaccine to individuals judged to be at risk of coming into contact with monkeypox (for example, gay and bisexual men with large numbers of sexual partners). It even had slight efficacy where vaccine take up was only 20%, increasing the three-month containment probability up to 60%. But if vaccine take up was increased to 80%, then the three-month containment probability also increased to 80%, and with better contact tracing to 90%.
In fact, if better contact tracing could be achieved, then the Ebola strategy would be the best and most economic (in terms of infections stopped per shot). But if this could not be achieved, then highly targeted pre-exposure vaccination was the most efficient strategy.
Pre-exposure vaccination involves post-exposure anyway. Given that the vaccine is effective at stopping infection for at least four days after exposure, and maybe for as long as 12 days, if blanket immunisation of at-risk people is achieved, it could nip infections in the bud.
As with PrEP, post-exposure prophylaxis becomes much less cost-effective if people at less risk of infection are vaccinated. In that scenario, it adds nothing extra.
The trick, as it was with PrEP, will be to target the people who really are at risk of monkeypox without stigmatising them, and to reassure the people who are not at risk so they don’t demand vaccines unnecessarily. So far, it’s the demand side of things that needs to be emphasised more.
There are signs in the UK that this is now being taken more seriously. In a call by the UK Health Security Agency and NHS England today it was announced that 80 STI clinics in England now have vaccine, including 18 in London. Clinics are considering putting on large vaccine ‘pop-ups’, as was done with COVID, to which members of the gay and bisexual male community at risk will be invited.
Monkeypox is still overwhelmingly concentrated among gay men; and HIV infection, even when virologically controlled, is a significant risk factor. Sexually active and HIV-positive gay men should be encouraged to seek vaccination as soon as it is available.