The U.S. heath secretary recently declared monkeypox as a public health emergency, paving the way for emergency use authorizations of additional vaccines or vaccine regimens to fight the disease.
The same day, Food and Drug Administration Commissioner Robert Califf said that the U.S. government is seriously considering stretching the very limited supply of Bavarian Nordic’s Jynneos vaccine — the only vaccine licensed against monkeypox in the U.S. — by changing the way it is given. Instead of giving a full dose subcutaneously (into the fat layer under the skin), a lower dose of the vaccine could be given intradermally (injecting the vaccine within the skin). The FDA may soon issue an emergency authorization for Jynneos to be administered in this way.
Given the precarious state of affairs with respect to the U.S. stockpile for Jynneos and Bavarian Nordic’s limited capacity to quickly make more doses, the U.S. has limited options. This dose-sparing strategy could begin to address a public health need for men who have sex with men, who are at higher risk for acquiring the infection. If the vaccine can be administered at lower doses at no risk to effectiveness, lower-dose intradermal injections make sense.
But this strategy could also backfire. If there is a risk to effectiveness, it may be better to focus the available full doses of vaccine on individuals at highest risk — men who have sex with multiple male partners — to provide the best chance of getting the outbreak under control.
Uncertainties in the effectiveness of Jynneos will be magnified by switching to a new mode of administering a lower dose outside of a clinical trial. While the data support Jynneos as effective in reducing the severity of monkeypox, the data do not show that it prevents mild disease or transmission of the monkeypox virus. Indeed, in animal studies performed by Bavarian Nordic, even at the time of peak immune response, two doses of Jynneos did not prevent monkeypox infection or disease, though they did prevent the most severe disease and deaths. In addition, the vaccine’s ability to prevent monkeypox in the current outbreak, where a very high dose of virus infects people via mucosal surfaces (as occurs in sexual transmission), has not been studied in humans or animals. The existing studies provide even less confidence about effectiveness after just one dose — peak immune response is not achieved until two weeks after the second dose.
The largest study to support the proposed strategy of intradermal immunization involved a total of about 150 people who received both doses. About 20% of first-dose recipients didn’t get their second doses, likely related to high local reaction rates after the first dose. Study participants were evaluated for antibody responses to the vaccine strain virus (vaccinia) that are expected to track monkeypox antibody responses. Antibody levels were similar between recipients of the low-dose intradermal vaccine and those who received the normally delivered full-dose vaccine, although the criteria for the comparisons were less rigorous than the FDA normally uses for this type of comparison.
These antibody responses on their own, however, don’t predict protection against monkeypox.
In other studies, two doses of the Jynneos vaccine induced antibody titers in humans similar to one dose of the ACAM2000 vaccine (which is based on the vaccine that was used to eradicate smallpox), but the ACAM2000 vaccine proved much more protective against monkeypox challenge in vaccinated animals. There is also an uncertain relationship between the doses given in this study and that of the current vaccine, which can vary over an eightfold range, so using a 20% dose of vaccine for intradermal inoculation could either substantially underdose recipients (with a risk of lower effectiveness) or overdose them (with the potential for more side effects) relative to the vaccine given in the study of intradermal administration.
This study also reported lower long-term immune responses in those who received the lower-dose intradermal vaccine, raising concerns about the overall immune response to the intradermal lower dose vaccine.
Switching to intradermal administration is also complicated. Vaccines are not typically given intradermally in the U.S., and there is little margin for error. Mistakes could cause a lower dose of the vaccine to be delivered deeper than intended, with likely lower effectiveness. That’s why the worldwide vaccination campaign that led to the eradication of smallpox used a special needle, called a bifurcated needle, to provide consistent dosing, and why developers are exploring more reliable methods than needles and syringes for other vaccines that could be administered intradermally.
People who administer the vaccine intradermally would need special training, and even then may make mistakes. The FDA normally regulates vaccines paired with unusual delivery devices as combination products, which involve an extra set of assurances that the correct dose will be delivered to the right part of the body — assurances that likely would not be present in this case.
Vaccines by themselves won’t solve the monkeypox outbreak. Concern over stigma associated with monkeypox has made it more difficult to target messaging to the groups at highest risk both of getting monkeypox and sustaining transmission — individuals who have many sexual partners who, so far, have predominantly been men who have sex with men. While there are spillover cases to people not in this risk group, the likelihood that sustained transmission will arise from these other cases is presently low.
Without public health campaigns that provide clear information to the core high-risk group, there is even a possibility that vaccination will increase the incidence of risky behaviors — and a vaccine that is not highly effective could actually make things worse.
Other vaccines, including the ACAM2000 (which has been associated with heart complications) and the Japanese LC16m8 vaccines, may have an important role to play as well, but like Jynneos they are in short supply.
Monkeypox isn’t going away, so the U.S. government needs to urgently evaluate alternative strategies to augment the supply of monkeypox vaccines and deploy it effectively. In addition, more information is needed about antiviral drugs that might treat monkeypox, including antibody-based treatments such as vaccinia immune globulin.
The U.S. needs a concerted effort to make sure enough vaccines and therapeutics are available to address these needs and to reduce suffering. A hasty decision to try an unproven and risky strategy to stretch the existing vaccine supply may interfere with developing a national plan to quell this outbreak.
Philip Krause is an infectious diseases physician, a consultant to the World Health Organization, and a former deputy director of the U.S. Food and Drug Administration’s Office of Vaccines Research and Review. Luciana L. Borio is an infectious disease physician, a senior fellow for global health at the Council on Foreign Relations, and former director for medical and biodefense preparedness policy at the National Security Council. The authors have no links to any companies producing or evaluating any of the vaccines mentioned in this article.
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Low-dose monkeypox vaccination presents several challenges - STAT - STAT
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