The Japanese monkeypox vaccine

Thoughts on the monkeypox vaccine program and what is the actual cause of death in this generally very mild illness?

Vaccine development is kind of a random process. It is based on guesswork. You guess that something might work, and then you test it out (inject it) in animals and then people. And you watch what happens.

Or you passage a virus through many animals or cell cultures and see what you get in the end as it naturally mutates in the process. And you inject that into animals, then people.

A very good paper from Canada reveals that of those vaccines that were recently approved by FDA to start a Phase 2 trial, only 10% got a license within ten years. (And 42% of those were for avian flu vaccines that did poorly in clinical trials but were approved for political reasons.). 90% essentially failed. Because when you rely on trial and error, most of your creations fail. But when the US deemed COVID a major threat, almost every vaccine sponsored by the USG succeeded. To our detriment and dismay.

Each vaccine is unique. And when you put 2 or 3 vaccine antigens (or up to 6-7 these days) in the same vial, you can’t predict ahead of time if they will work well together or not.

A lot of obvious experimentation (to answer obvious questions) has not been done because it might reveal an answer no funder wants to see.

I should not really generalize about vaccines because they are very different from each other.

But in terms of monkeypox, the 2nd vaccine the WHO revealed today that it plans to use deserves a look. Below are selected passages from the 2006 article I linked to on how the LC16 vaccine was developed (from the same German grandparent vaccine as MVA-BN) in Japan to try and avoid the 20 cases of encephalopathy (most of whom were infants and died) per million doses of smallpox vaccine administered, that occurred in the 1960s and earlier.

This article is a fairly comprehensive review. It reveals in exquisite detail the trial and error approach to vaccine development. It also reveals the very limited info on how this and other smallpox vaccines may or may not have prevented monkeypox infections. And it reveals that myocarditis, as well as encephalitis, has been a known serious side effect of smallpox vaccines.

I read 2 newer reviews of monkeypox vaccines but they were more superficial. So I leave you with the best quotes from this paper to learn more about the second vaccine WHO plans to push out for monkeypox, if it gets funding.

Note: the US and Japan have each manufactured tens of millions of doses of each of the two vaccines being offered: MVA-BN and LC16. The MVA-BN is frozen as liquid (longterm storage) or freeze-dried (new method). I do not know whether they have expiration dates when in long-term storage.

I do not know if the side effects of the vaccine, which are significant, are worse than the disease.

I also wanted to let you know that MVA-BN causes problems in HIV positive recipients, as found in prelicensure trials in the FDA file.

Finally, if this generally mild viral illness is killing people, what is the cause of death? Does it only cause death in severely immune suppressed patients? Are babies dying due to dehydration? Do we need to treat babies with fluids rather than give them a vaccine that was never tested in babies? Lots of unanswered questions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115618/

Japan has retained a national stockpile of LC16m8 since conditionally licensing it in 1975 (unconditional licensure was granted in 1980). The government decided to increase the volume of its LC16m8 stockpile in 2000 in response to a resurgence of monkeypox in Africa, and again in early 2002 in response to terrorist threats in the US and other regions of the world.

Finally, it has recently been reported by Saijo et al. that LC16m8 and Lister provided protection from disease in monkeys challenged with severe intranasal monkeypox [72].

In recent clinical trials evaluating Dryvax, myopericarditis, a serious adverse event rarely reported in the past, was found to occur at high rates among primary vaccinees [78], [79]. Through careful evaluation of vaccinees for both clinical and subclinical symptoms, this reaction was identified in up to 1/145 primary vaccinees, prompting the addition of a black box warning to the package insert of Dryvax in 2004 [80]. This discovery has further fueled the drive to identify smallpox vaccines with improved safety profiles.

Unfortunately, subclinical or overt myopericarditis was also found to occur at high rates in both the ACAM2000 and Dryvax control groups [79], [80]. In addition, one vaccinee given the experimental vaccine experienced a new onset seizure 8 days postvaccination [75]. In another recent Phase II study, myopericarditis developed in one subject 10 days after vaccination with 6.8 × 10⁷  pfu/mL of ACAM2000 [83].

Given the disappointing safety findings of cell culture-derived second-generation vaccines, focus has once again shifted to third-generation vaccines such as LC16m8 and MVA (IMVAMUNE, Bavarian Nordic; and MVA3000, Acambis) as a potential means of replenishing national stockpiles. The Japanese government recently announced that it will significantly expand its national stockpile of LC16m8, affording protection for 56 million people in the event of a bioterrorist attack [84].

Although the threshold titer of neutralizing antibodies needed for protection is unknown [23], [87], it was recently shown that human vaccinia-specific antibodies passively transferred to non-immunized macaques offered protection against a lethal monkeypox challenge [95].

The duration of humoral and cell-mediated protective immunity afforded by smallpox vaccination remains unknown, yet there is both empirical [96], [97] and experimental [43], [98], [99], [100] evidence that some degree of immunity to smallpox persists for several decades postvaccination. In addition, Hammarlund and colleagues recently reported that smallpox vaccination as much as 48 years pre-exposure conferred immunity to humans exposed to monkeypox [101]. No data on the duration of long-term immunity to LC16m8 are currently available, however, immunity duration will be an important consideration for all new smallpox vaccine candidates.

While the biodefense-focused quest for a safe and effective smallpox vaccine is urgent, only the eventual outcomes of controlled clinical and nonclinical studies of new smallpox vaccine candidates will ensure their suitability for use in humans should smallpox recur in the future.