Danger of Mixing!? The Relationship Between Vaccinia Virus and Monkeypox
While researching the horizontal transmission of the smallpox vaccine, which I covered in a previous article, I became curious about various things regarding the "vaccinia virus." As I investigated further, I found descriptions related to monkeypox, and I am concerned about future developments.
Is the smallpox vaccine not something to be taken lightly!?
First, I checked the vaccination section in the "Smallpox Response Guidelines" provided by the Ministry of Health, Labour and Welfare.
Smallpox Response Guidelines (5th Edition) May 14, 2004https://www.mhlw.go.jp/kinkyu/j-terr/2004/0514-1/dl/01.pdf
The advice sheet in the appendix (pp. 57-61) describes the criteria for deciding whether to vaccinate as follows. This concerns contact with smallpox patients who have a high mortality rate, and is different from contact with monkeypox patients, but there was something worth noting regarding the description for people who had no contact (anxious citizens).
1. First-degree contact
- Contact where exposure to the source of infection is considered to have occurred via droplets and aerosols of secretions from a smallpox patient, or materials contaminated by them.
Q2: Do I need to get a smallpox vaccination?
A2: You need to get vaccinated promptly. Vaccination is considered most effective when performed within 4 days of contact with a patient infected with smallpox.
2. Second-degree contact
- Contact with a lower risk of infection, such as contact via air.
- Temporary or remote contacts are not treated as second-degree contacts.
Q2: Do I need to get a smallpox vaccination?
A2: You need to get vaccinated.
3. Secondary contact
- In cases of close contact with a first-degree contact.
Q2: Do I need to get a smallpox vaccination?
A2: You need to get vaccinated unless vaccination is considered inappropriate.
Anxious citizens
Q1: Why is no special treatment necessary?
A1: Because there is no close contact with a smallpox patient, it is considered that there is almost no risk of infection.
Q2: Should I get a smallpox vaccination?
A2: There is no need to get vaccinated.Since smallpox vaccines can, albeit rarely, cause side effects including fatal ones, it is decided that they should not be administered to anyone other than those at high risk of infection.
It states, "It is decided that they should not be administered to anyone other than those at high risk of infection." In other words, I believe it is not something you get just because you are worried.
The section on vaccination (pp. 62-) states the following.
II Smallpox Vaccine
1. Overview of the vaccine
- The smallpox vaccine is a live vaccine created by attenuating the vaccinia virus, which belongs to the Orthopoxvirus genus of the Poxviridae family, the same genus as the smallpox virus.
- In Japan, the LC16m8 strain is used as the vaccinia virus strain, which is said to have fewer side effects compared to those used in the United States.
2. Efficacy
- When vaccination is performed appropriately, the efficacy rate in susceptible individuals is almost 100%.
- Even in post-exposure vaccination, if performed within 4 days of exposure, it is possible to prevent infection or reduce symptoms.
3. Inappropriate candidates for vaccination, normal reactions after vaccination, side effects, etc.
- Because there is a possibility of vaccinia virus infection from a vaccinated person, consider the safety of people who have contact with them until the vaccination site has completely healed. Avoid contact with people who have eczema, atopic dermatitis, underlying diseases, or especially severe immunodeficiency.
Here too, it is written that "there is a possibility of vaccinia virus infection from a vaccinated person."
Considering these descriptions, it seems the normal procedure for monkeypox would also be to establish an environment where vaccination can be provided promptly to those who have been exposed, rather than encouraging widespread smallpox vaccination.
Risks of the vaccinia virus
The website of the Consulate General of Japan in New York also has a Q&A regarding smallpox.
Since it is written based on information from the U.S. Centers for Disease Control and Prevention (CDC), it differs from the Japanese vaccine, but I think it is useful for information regarding the vaccinia virus.
Q: Can you get smallpox from the vaccine?
A: No. The smallpox vaccine does not contain the smallpox virus and does not cause or spread smallpox. However, the vaccine contains a different type of virus called vaccinia, and because the virus is alive, it can spread to parts of the body other than the vaccination site or to other people's bodies. You need to wash your hands, carefully dispose of used bandages, and properly treat the vaccination site.
Q: Can the vaccine virus be transmitted from a vaccinated person?
A: Yes.If you touch the vaccination site or used bandages, the vaccine virus can be transmitted. The vaccine virus is not airborne, but it can cause rashes, fever, headaches, and body aches.
Q: How safe is the smallpox vaccine?
A: The smallpox vaccine is the best protection if you are exposed to the smallpox virus. Most people usually experience mild reactions (after vaccination) such as arm discomfort, fever, and body aches. In recent trials, one in three vaccinated people felt ill enough after vaccination to miss work, miss school, cancel leisure activities, or experience sleep disturbances.Furthermore, the vaccine carries risks. In the past, about 1,000 out of every 1 million people vaccinated for the first time experienced serious side effects, though not life-threatening. These reactions include strong reactions (toxic or allergic) at the vaccination site and the transmission of the "vaccinia virus" (live virus in the smallpox vaccine) to other parts of the body or to other people. (omitted below)
Regarding transmission, it is written that it is due to "contact with the vaccination site" and that there is no airborne transmission, but what about droplets? In the paper on the mumps vaccine, it gave the impression that transmission occurred within the household without necessarily having to touch things directly (see below).
Currently, vaccines for monkeypox prevention are being administered in places like New York, but these are not the smallpox vaccines used in the past; they are "Jynneos" from Bavarian Nordic. The FDA approved it as the first vaccine for monkeypox prevention on September 24, 2021.
According to the Ministry of Health, Labour and Welfare's website, it states that "On July 17, 2021, the U.S. International Health Regulations (IHR) focal point notified the Pan American Health Organization (PAHO: WHO Regional Office for the Americas) that a human imported case of monkeypox had been confirmed in Dallas, Texas." It adds, "This is the first time a monkeypox patient has been discovered in a traveler to the United States, and it is the first case reported in the U.S. since the 2003 outbreak."
With the first case reported in the U.S. in July and the first monkeypox vaccine approved in September, the feeling that this was too well-prepared is concerning. This vaccine reportedly contains a modified version of the vaccinia virus called Modified Vaccinia Ankara.
A smallpox-derived vaccine for COVID?
While researching the vaccinia virus, articles appeared stating that it is being used in other vaccine development and treatment research. For example, COVID vaccines.
This is a Tokyo Metropolitan Government report (February 1, 2021) stating that they are developing a recombinant live vaccine by introducing the SARS-CoV-2 gene into the attenuated smallpox vaccine "vaccinia virus" DIs strain.
Smallpox vaccines have a track record of being used for 200 years. The DIs strain used this time is a further attenuated version of previous vaccines, and there are almost no side effects.
There is an explanation that "smallpox vaccines have a 200-year track record, and the DIs strain is further attenuated, so there are almost no side effects," but I do not think one can say there are no side effects just because there is a 200-year track record. This is because even with a 200-year track record, the same strain of vaccine has not been used the entire time.
In Japan, routine smallpox vaccination was abolished after 1976, and since then, it should have been manufactured for stockpiling with almost no opportunity for use. The vaccine strains have also become new, and our bodies have likely changed due to changes in food and other factors. If there is no track record of administration to current humans, hasn't the safety not been confirmed?
The LC16m8 strain vaccine, which was approved on July 29 for use with the aim of preventing the onset and severity of "monkeypox," had its revised package insert and Risk Management Plan (RMP) published on August 3.
Attenuation of strains and thereafter
When researching smallpox vaccine strains, the circumstances under which Dr. So Hashizume developed LC16m8 at the then-Chiba Prefectural Serum Institute were written in an article titled "Development of Attenuated Smallpox Vaccine Strain LC16m8 and the Current Status of This Vaccine" (2011).https://www.jspid.jp/wp-content/uploads/pdf/02302/023020181.pdf
Among those attenuated using the Lister strain as the parent strain, LC16 was extremely attenuated to the same degree as the DIs strain. From there, it went from LC16 to LC16mO to LC16m8, but it is written that as of 2011, it was hardly used.
Based on the results of this smallpox research team, it received manufacturing approval from the Ministry of Health and Welfare in 1975 and became available as a product, but in our country, the law was amended in 1976 and routine smallpox vaccination was discontinued, so the LC16m8 vaccine was actually hardly used, and it became one of the vaccines stockpiled for emergencies. Although this vaccine was not used generally, it was used for some researchers who handle Orthopox group viruses and for Self-Defense Forces personnel dispatched overseas.
After that, Chiba Serum decided to discontinue its business, and the manufacturing of the stockpiled vaccine was transferred to the Chemo-Sero-Therapeutic Research Institute (Kaketsuken).
The LC16m8 vaccine was developed and manufactured at Chiba Serum, but in September 2002, Chiba Serum decided to discontinue its business, and the manufacturing of this vaccine was transferred to Kaketsuken in July 2002. In our country, following the terrorist attacks in the United States in September 2001, the manufacturing of smallpox vaccine was resumed, and in March 2002, it was decided to be stockpiled nationally. Therefore, from July 2002 onwards, the manufacturing of the stockpiled vaccine was continued at Kaketsuken.
Perhaps anticipating that the demand for this vaccine would be needed globally, Kaketsuken also referred to the advice of the U.S. FDA for this vaccine manufacturing, constructed a new facility that meets the latest manufacturing facility standards, and it is already in operation.
Although it is written casually that "it is assumed that there will be a global demand for this vaccine" and "FDA advice," this is an article written in 2011.
Speaking of the Chemo-Sero-Therapeutic Research Institute (Kaketsuken), I remember they caused some problems, and in 2015 it was revealed that they had been manufacturing blood products and other items using methods different from those approved for many years, which became a major issue.
https://www.pmda.go.jp/files/000212645.pdf
After that, the Chemo-Sero-Therapeutic Research Institute (Kaketsuken), which had been requested by the Ministry of Health, Labour and Welfare to transfer its business, established a new company and transferred its main businesses such as vaccines and plasma derivatives. The new company began operations as a consolidated subsidiary of Meiji Holdings (HD). Then, on July 2, 2018, it transferred its main businesses, including the pharmaceutical business, to "KM Biologics," which is funded by Meiji Holdings, a group of seven companies in Kumamoto Prefecture, and the Kumamoto Prefectural Government.
The manufacturer and distributor of the dried cell-cultured smallpox vaccine LC16 "KMB" approved this time is "KM Biologics." I am curious about how the vaccine business has been conducted since LC16m8, developed by Dr. So Hashizume, was taken over from Chiba Serum through Kaketsuken. Especially considering what Kaketsuken was doing with blood products, I cannot easily trust them. They have not even conducted new clinical trials regarding monkeypox.
Materials regarding dried cell-cultured smallpox vaccine LC16 "KMB"https://www.pmda.go.jp/drugs/2022/P20220802001/261976000_15500EZZ00960_K100_1.pdf
The clinical trial that confirmed its efficacy against monkeypox was a clinical trial (Phase 1/2 study (NCT00103584)) conducted in the United States on 154 healthy adults with no history of smallpox vaccination, and it refers to a 2011 paper.
In Japan, there are clinical research results from 2002-2005 where the smallpox vaccine LC16m8 was administered to 1,529 Self-Defense Forces personnel with no history of smallpox vaccination and 1,692 Self-Defense Forces personnel with a history of smallpox vaccination. And a post-marketing survey (2015) conducted on 268 adults (Self-Defense Forces personnel, 196 first-time vaccinations, 71 re-vaccinations, 1 unknown). The number of people is small, and there are no cases of people who received this vaccine after receiving the COVID-19 vaccine.
"Oncolytic virus" being researched by Astellas Pharma
While researching vaccinia virus, I found another study that caught my attention. In 2018, Astellas Pharma seems to have acquired the development rights for "ASP9801," an oncolytic virus that attacks cancer using a virus that proliferates only within cancer cells, from Tottori University. On the company's website, it is stated under the "Cancer Immunology" section below that it has progressed to Phase 1 clinical trials.
https://www.astellas.com/jp/partnering/primary-focus
When handling genetically modified organisms, it seems that an application for approval is required, and the application for approval and the notification of results are published on the site below. Something very concerning was written there. The agriculture, forestry, and fisheries field is also in a state of flux, but this time I will focus on the use of "attenuated vaccinia virus LC16mO strain" in the pharmaceutical field.
◆Pharmaceutical field◆ ○Approved on November 26, 2019
Astellas Pharma has applied for the use of attenuated vaccinia virus LC16mO strain.
Application for approval
https://www.biodic.go.jp/bch/download/lmo/R1.11.26_iyaku_ap1.pdf
Notification of results
https://www.biodic.go.jp/bch/download/lmo/R1.11.26_iyaku_sp1.pdf
From the notification of results
Management of patients after administration
(5) After administration of this genetically modified organism, etc., disinfect the administration site, and cover the injection site with a waterproof airtight dressing material, etc., so that the spread of this genetically modified organism, etc., discharged from the administration site to the environment is minimized. (6)
Place the administered patient in a general private room clearly separated from other sections (hereinafter referred to as "private room"), and after administration, until the behavior of the discharge, etc., of this genetically modified organism, etc., becomes clear, keep the release of excreta, etc., containing this genetically modified organism, etc., from the patient into the environment to a minimum, and perform management to reduce the risk of transmission (hereinafter referred to as "private room management"). (10) Until the behavior of the discharge, etc., of the administered genetically modified organism, etc., becomes clear,
periodically conduct tests for the discharge, etc., of this genetically modified organism, etc., on blood, urine, feces, or saliva, etc.. (11) If unexpected proliferation or transmission of the genetically modified organism, etc., is suspected, conduct necessary tests to confirm the presence or absence of this genetically modified organism, etc., in blood, body fluids, secretions, or excreta, etc.
. 2. Biological Diversity Impact Assessment Report (3) Information regarding the use, etc., of genetically modified organisms, etc. Domestically and internationally, there is no track record of using this genetically modified organism, etc., so far
. (4) Biological diversity impact assessment This genetically modified organism, etc., is considered unlikely to show pathogenicity for the following reasons. ・
Proliferation in the environment is limited unless this genetically modified organism, etc., co-infects with other viruses belonging to the genus Orthopoxvirus (hereinafter referred to as "Orthopoxvirus genus viruses"), but the presence of Orthopoxvirus genus viruses has not been detected in Japan at present
. The targets that this genetically modified organism, etc., infects are limited to some mammals such as humans, and
the possibility of co-infection of this genetically modified organism, etc., and Orthopoxvirus genus viruses in the same cell in the body is low, so it is considered that the possibility of horizontal transfer of nucleic acids is low. II. Outline of Review 1. Regarding the results of biological diversity impact assessment (4) Properties of horizontal transfer of nucleic acids Since the replication of this genetically modified organism, etc., is completed within the cytoplasm of the infected cell and does not migrate to the nucleus, there is no possibility that the viral genome and donor nucleic acid of this genetically modified organism, etc., will be integrated into the genome of the infected cell. The targets that this genetically modified organism, etc., infects are some mammals such as humans, similar to the LC16mO strain, but since the LC16mO strain and Lister strain are not established in the natural environment and the proliferation of this genetically modified organism, etc., in normal cells is suppressed compared to the LC16mO strain and Lister strain, it is considered that even if it leaks into the environment, it will gradually disappear from the environment. There is also a possibility that this genetically modified organism, etc., that has leaked into the environment may produce a self-replicating virus through homologous recombination. However, for that to happen, it is necessary for this genetically modified organism, etc., and an Orthopoxvirus genus virus to co-infect, so it is considered that the possibility is low.
There is no track record of using this genetically modified organism, etc., so far, and the application has been made on the premise that it will not co-infect with an "Orthopoxvirus genus virus." However, the monkeypox virus is an Orthopoxvirus genus virus.
The fact that clinical trials have progressed to Phase 1 means that some people have already been administered the virus. What would happen if this vaccinia virus and the monkeypox virus were to come together? It is possible that other research like this is being conducted as well.
Another point mentioned is transmission. The fact that the study states that if transmission of the vaccinia virus is suspected, one should "confirm the presence or absence of these genetically modified organisms in blood, body fluids, secretions, or excreta" suggests that the vaccinia virus from smallpox vaccine recipients could potentially be transmitted through sewage or other means. I believe this means that if many people are vaccinated, it is not yet known how it might spread.
Based on the above, the issue of vaccinia virus transmission is extremely concerning.