Mpox Virus Infection and Vaccination: Immunopathogenesis and Exploring the Link to Neuropsychiatric Manifestations

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I would like to thank the authors for their submission and allowing me to review their work.

This is an interesting study on an important topic. However, I would be grateful if you could add further explanations and changes on the following points:

1) ABSTRACT:

In my opinion, the abstract is too long. It should briefly summarize the keys points of the study.

2) ABSTRACT: Page 1, line 47

Acronyms should be explained the first time they appear in the text.

3) INTRODUCTION: Page 2, line 73

I suggest discussing whether there are differences in clinical manifestations and long-term outcomes between children and adults.

4) INTRODUCTION: Page 2, line 100

What type of review is it? Please, clarify.

5) METHODOLOGY: Page 3, line 103

I suggest clearly describing the inclusion and exclusion methods of the study.

6) PSYCHIATRIC MANIFESTATIONS IN MPOX PATIENTS: Page 12, line 380

I suggest that it should be better emphasized that all serious illnesses can cause depression, anxiety and stress; therefore, a direct correlation between Mpox and psychiatric symptoms should be analyzed in more detail.

7) Page 15, line 472

It would be beneficial to provide more explanation on how the vaccines differ in terms of mechanism and efficacy.

8) Page 19, line 703

I suggest providing more details on the future prospects of this study.

Author Response

Response to reviewer comments

Reviewer 1

I would like to thank the authors for their submission and allowing me to review their work.

This is an interesting study on an important topic. However, I would be grateful if you could add further explanations and changes on the following points:

 

1) ABSTRACT:

In my opinion, the abstract is too long. It should briefly summarize the keys points of the study.

Response: Thanks for the note

The abstract was summarized and adjusted

Background and Aim

Monkeypox (Mpox) is a viral disease mainly found in central and western Africa, with symptoms similar to smallpox but distinguished by early lymph node swelling specific to Mpox. This review summarizes the neuropsychiatric manifestations of Mpox infection and vaccination, along with management approaches.

Method

We searched different databases such as PubMed, Scopus, WoS, and google scholar about the neuropsychiatric manifestations of Mpox disease and their associated strategies of management.

Result and conclusion

Mpox can cause a wide range of neurological symptoms. These range from mild symptoms like headaches, muscle aches, fatigue, and pain to severe symptoms, including seizures, blindness, photophobia, delirium, coma, encephalitis, and transverse myelitis. It is essential to distinguish Mpox from smallpox and other Orthopox viruses. Psychiatric issues, such as stigma, disfigurement, isolation, and physical pain, are common in Mpox patients. To address these, healthcare providers should provide accurate information, counseling, and virtual support. Neurological side effects were associated with the previous smallpox vaccine, which offered cross-protection against Mpox. This vaccine has since been replaced by ACAM2000, which has fewer neurological risks. Mpox-related neurological symptoms are generally managed with supportive care, including NSAIDs, antibiotics, antiepileptics, and sedatives for seizures. Antivirals like acyclovir are also used. Severe cases may require hospitalization or intubation. So, we recommend early diagnosis, isolation, and prompt treatment, as Mpox spreading to the central nervous system can lead to serious and potentially fatal complications.

2) ABSTRACT: Page 1, line 47

Acronyms should be explained the first time they appear in the text.

Response: Corrected

3) INTRODUCTION: Page 2, line 73

I suggest discussing whether there are differences in clinical manifestations and long-term outcomes between children and adults.

Response: Thanks for the note.

The differences in clinical manifestations between children and adults was added.

4) INTRODUCTION: Page 2, line 100

What type of review is it? Please, clarify.

Response: Thanks for the note

Our review is narrative review. It's type was added in the introduction part.

5) METHODOLOGY: Page 3, line 103

I suggest clearly describing the inclusion and exclusion methods of the study.

Response: Thanks for the note

The inclusion and exclusion criteria were added.

6) PSYCHIATRIC MANIFESTATIONS IN MPOX PATIENTS: Page 12, line 380

I suggest that it should be better emphasized that all serious illnesses can cause depression, anxiety and stress; therefore, a direct correlation between Mpox and psychiatric symptoms should be analyzed in more detail.

Response: Thanks for the note

We reported only the studies that analyzed the psychiatric manifestations in mpox patients only. And we stated that "it is crucial to highlight that this association does not automatically imply causation".  

7) Page 15, line 472

It would be beneficial to provide more explanation on how the vaccines differ in terms of mechanism and efficacy.

Response: Thanks for the note

Related paragraph was added

8) Page 19, line 703

I suggest providing more details on the future prospects of this study.

Response: Thanks for the note

Related paragraph was added

 

Reviewer 2 Report

Comments and Suggestions for Authors

Hetta et al. try to review Mpox virus infection and vaccination

 

A review on neuropsychiatric manifestations is welcome. In addition, the natural immune response is further important.

In general, a more broadly citation of the recent literature is recommended.

 

However, the review on (prophylactic) vaccination must be reevaluated with care and rewritten.

 

As Hetta et al. write “Notably, till now Mpox affects children and young adults mainly”. As many of these children suffer from malnutrition and young adults may be HIV positive and perhaps homosexual. Is a replicating vaccine really the choice for these individuals ?

In the introduction it was noted that “Variable neurological complications have been reported with the smallpox vaccine which was used in the past to give cross-protection against Mpox. Now it has been replaced by ACAM2000 which has less neurological complications”.

 

Now ACAM2000 is a replicating vaccine with a very bad record in healthy young adults resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death (1, 2). In their conclusion Hetta et al. wrote that “In conclusion, there are diverse neurological complications of the smallpox vaccine, the severe manifestations are rare especially with the new generation of the vaccine (ACAM2000 and JYNNEOS). 

The reviewer has problems to understand that Hetta et al. put a replicating vaccine (ACAM2000) and possible other replicating vaccines that were not tested so extensively as ACVAM200 in the same “basket” with a non – replicating vaccine (JYNNEOS ) that was used in HIV patients without any problems. Hence, the individuals to be vaccinated against Mpox are not healthy young US citizens. A critical review may look quite different.

 

1.             McNeil MM, Cano M, E RM, Petersen BW, Engler RJ, Bryant-Genevier MG. 2014. Ischemic cardiac events and other adverse events following ACAM2000((R)) smallpox vaccine in the Vaccine Adverse Event Reporting System. Vaccine 32:4758-65.

2.             Decker MD, Garman PM, Hughes H, Yacovone MA, Collins LC, Fegley CD, Lin G, DiPietro G, Gordon DM. 2021. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. Vaccine 39:5541-5547.

 

Author Response

Reviewer 2

Hetta et al. try to review Mpox virus infection and vaccination

A review on neuropsychiatric manifestations is welcome. In addition, the natural immune response is further important.

In general, a more broadly citation of the recent literature is recommended.

However, the review on (prophylactic) vaccination must be reevaluated with care and rewritten.

As Hetta et al. write “Notably, till now Mpox affects children and young adults mainly”. As many of these children suffer from malnutrition and young adults may be HIV positive and perhaps homosexual. Is a replicating vaccine really the choice for these individuals?

Response: Thanks for the note

No, replicating vaccine like ACAM2000 or APSV are not allow for children or immunocompromised patients such as HIV patients. Only JYNNEOS vaccine was preferred in these situations. A related paragraph was added in details to cover this point.

APSV was historically used to provide protection against smallpox, and by extension, it was also believed to offer some cross-protection against Mpox, which is caused by a related orthopoxviruses. APSV contains live vaccinia virus and works by stimulating the immune system to produce antibodies against vaccinia, offering immunity against smallpox and, to a lesser extent, other orthopoxviruses such as Mpox. However, due to safety concerns, particularly the risk of serious side effects such in immunocompromised patients as neurological complications, APSV has largely been replaced by newer, safer vaccines like ACAM2000 and JYNNEOS [102,103].

 ACAM2000 is a modified live vaccinia virus vaccine. ACAM2000 works by stimulating an immune response through viral replication in the body, which can result in stronger immune activation. While it is safer than APSV, it still carries risks of severe side effects like myocarditis, pericarditis, and skin infections. It was used as a replacement for APSV but is still not recommended for individuals with certain health conditions (such as immunocompromised individuals, pregnant women. ACAM2000 is given as a single dose by multiple puncture technique with maximum antibody titer after 28 days [103,104].

JYNNEOS is the safest of the three. It is a non-replicating, attenuated vaccine induces immunity by stimulating the production of neutralizing antibodies without the risk of causing active infection. Subsequently, JYNNEOS is preferred for high-risk populations, including pregnant women, and people with weakened immune systems because it doesn't pose the same risks of severe complications. For children, JYNNEOS also is the preferred choice. This is because it is a non-replicating, attenuated vaccine, which makes it safer for young children compared to other vaccines. JYNNEOS is administered by subcutaneous injection as a 2-dose series delivered 28 days apart and vaccine protection is not conferred until 2 weeks after receipt of the second dose [103,104]. 

 

 

 

In the introduction it was noted that “Variable neurological complications have been reported with the smallpox vaccine which was used in the past to give cross-protection against Mpox. Now it has been replaced by ACAM2000 which has less neurological complications”.

Now ACAM2000 is a replicating vaccine with a very bad record in healthy young adults resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death (1, 2). In their conclusion Hetta et al. wrote that “In conclusion, there are diverse neurological complications of the smallpox vaccine, the severe manifestations are rare especially with the new generation of the vaccine (ACAM2000 and JYNNEOS).

The reviewer has problems to understand that Hetta et al. put a replicating vaccine (ACAM2000) and possible other replicating vaccines that were not tested so extensively as ACVAM200 in the same “basket” with a non – replicating vaccine (JYNNEOS) that was used in HIV patients without any problems. Hence, the individuals to be vaccinated against Mpox are not healthy young US citizens. A critical review may look quite different.

Response: We are sorry for this unintentional mistake.

We removed this confusion and added these sections

*APSV was historically used to provide protection against smallpox, and by extension, it was also believed to offer some cross-protection against Mpox, which is caused by a related orthopoxviruses. APSV contains live vaccinia virus and works by stimulating the immune system to produce antibodies against vaccinia, offering immunity against smallpox and, to a lesser extent, other orthopoxviruses such as Mpox. However, due to safety concerns, particularly the risk of serious side effects such in immunocompromised patients as neurological complications, APSV has largely been replaced by newer, safer vaccines like ACAM2000 and JYNNEOS [102,103].

 ACAM2000 is a modified live vaccinia virus vaccine. ACAM2000 works by stimulating an immune response through viral replication in the body, which can result in stronger immune activation. While it is safer than APSV, it still carries risks of severe side effects like myocarditis, pericarditis, and skin infections. ACAM2000 had a very bad record in healthy young adults resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death [104,105]. It was used as a replacement for APSV but is still not recommended for individuals with certain health conditions (such as immunocompromised individuals, pregnant women. ACAM2000 is given as a single dose by multiple puncture technique with maximum antibody titer after 28 days [103,104].

JYNNEOS is the safest of the three. It is a non-replicating, attenuated vaccine induces immunity by stimulating the production of neutralizing antibodies without the risk of causing active infection. Subsequently, JYNNEOS is preferred for high-risk populations, including pregnant women, and people with weakened immune systems because it doesn't pose the same risks of severe complications. For children, JYNNEOS also is the preferred choice. This is because it is a non-replicating, attenuated vaccine, which makes it safer for young children compared to other vaccines. JYNNEOS is administered by subcutaneous injection as a 2-dose series delivered 28 days apart and vaccine protection is not conferred until 2 weeks after receipt of the second dose [103,104].

 

 

*JYNNEOS is the preferred choice for individuals who need protection after exposure to monkeypox, as it offers protection without the risks of severe side effects like myocarditis or encephalitis, which are more common with live virus vaccines like ACAM2000. However, ACAM2000 may still be used in certain high-risk populations under specific circumstances, but it is not the first-line choice for post-exposure prophylaxis due to these concerns [102,103].

 

 

*In conclusion, there are diverse neurological complications of the smallpox vaccine, though severe complications are less common with ACAM2000. However, ACAM2000 may still be used in certain high-risk populations under specific circumstances, but it is not the first-line choice. JYNNEOS stands out as the safest and most effective option, especially for vulnerable individuals.

 

 

1. McNeil MM, Cano M, E RM, Petersen BW, Engler RJ, Bryant-Genevier MG. 2014. Ischemic cardiac events and other adverse events following ACAM2000((R)) smallpox vaccine in the Vaccine Adverse Event Reporting System. Vaccine 32:4758-65.

 

2. Decker MD, Garman PM, Hughes H, Yacovone MA, Collins LC, Fegley CD, Lin G, DiPietro G, Gordon DM. 2021. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. Vaccine 39:5541-5547.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

This is a very interesting review. But I have some questions.

1) The abstract is too long. Many journals require maximum of 200-300 words. It is also not a good idea to have such a long abstract as doctors and scientists often don't have time to read long abstracts. Therefore, if your abstract is too long, it may just be bypassed.

2) The official name of smallpox is variola. I don't see that word anywhere in the paper. 

https://www.cdc.gov/smallpox/index.html

3) The sentence on 476-477 is very awkward and may be grammatically wrong. The word "got" is seldom used in proper English.  It should be rephrased differently. "Have" is a better word

4) On line 519-520, "[Dryvax] is replaced by ACAM2000, which has less neurological complications". How was the "less neurological complications" found? Clinical studies? This article says that both have similar safety profiles 

https://www.cidrap.umn.edu/anthrax/cdc-retires-one-old-smallpox-vaccine-keeps-another

5) We must understand the history of smallpox vaccine. The first smallpox vaccine discovered by Edward Jenner in the 18th century was cowpox. But somehow the first vaccine used for mass vaccination was horsepox. Somehow, the horsepox was mysteriously replaced by vaccinia. We don't know where =vaccinia came form.  Do you have any information on the neurological effects of cowpox and horsepox in comparison to the modern day vaccinia?  

6) Line 531, "Most of the cases recover" should be changed " Most of he patients in those cases recovered.."

7) Line 532 "Some cases have.." should be replaced by "Some of the patients in those cases have.."

Author Response

Response to reviewer 3 comments

Reviewer 3

This is a very interesting review. But I have some questions.

1) The abstract is too long. Many journals require maximum of 200-300 words. It is also not a good idea to have such a long abstract as doctors and scientists often don't have time to read long abstracts. Therefore, if your abstract is too long, it may just be bypassed.

Response: Thanks for the note

Adjusted to 234 words

 

Background and Aim

Monkeypox (Mpox) is a viral disease mainly found in central and western Africa, with symptoms similar to variola virus (smallpox) but distinguished by early lymph node swelling specific to Mpox. This review summarizes the neuropsychiatric manifestations of Mpox infection and vac-cination, along with management approaches.

Method

We searched different databases such as PubMed, Scopus, WoS, and google scholar about the neuropsychiatric manifestations of Mpox disease and their associated strategies of management

Result and conclusion

Mpox can cause a wide range of neurological symptoms. These range from mild symptoms like headaches, muscle aches, fatigue, and pain to severe symptoms, including seizures, blindness, photophobia, delirium, coma, encephalitis, and transverse myelitis. It is essential to distinguish Mpox from smallpox and other Orthopox viruses. Psychiatric issues, such as stigma, disfigurement, isolation, and physical pain, are common in Mpox patients. To address these, healthcare providers should provide accurate information, counseling, and virtual support. Neurological side effects were associated with the previous smallpox vaccine, which offered cross-protection against Mpox. This vaccine has since been replaced by JYNNEOS, which has fewer neurological risks. Mpox-related neurological symptoms are generally managed with supportive care, including NSAIDs, antibiotics, antiepileptics, and sedatives for seizures. Antivirals like acyclovir are also used. Severe cases may require hospitalization or intubation. So, we recommend early diagnosis, isolation, and prompt treatment, as Mpox spreading to the central nervous system can lead to serious and potentially fatal complications.

 

 

2) The official name of smallpox is variola. I don't see that word anywhere in the paper.

https://www.cdc.gov/smallpox/index.html

Response: Thanks for the note. Added.

 

3) The sentence on 476-477 is very awkward and may be grammatically wrong. The word "got" is seldom used in proper English.  It should be rephrased differently. "Have" is a better word

Response: Thanks for the note.Corrected.

 

4) On line 519-520, "[Dryvax] is replaced by ACAM2000, which has less neurological complications". How was the "less neurological complications" found? Clinical studies? This article says that both have similar safety profiles

https://www.cidrap.umn.edu/anthrax/cdc-retires-one-old-smallpox-vaccine-keeps-another

Response: Thanks for the note

The CDC article you're referring to notes that both Dryvax and ACAM2000 share similar safety profiles in some respects. Since both vaccines are derived from live vaccinia virus, they indeed share many safety concerns, such as the risk of myocarditis and pericarditis, autoinoculation (self-spreading the virus to other body parts), and complications in immunocompromised individuals or those with skin conditions. Both vaccines can trigger strong immune responses, and they both come with significant warnings regarding use in certain populations.

However, ACAM2000 was developed with enhanced production techniques, making it more standardized compared to the older Dryvax. This improvement aimed to provide more controlled dosing and consistent results, potentially making ACAM2000 safer to manufacture and administer on a large scale, though it still carries similar side effect risks to Dryvax. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5708a6.htm

For current safety and usage information on ACAM2000, the FDA’s official package insert, and Q&A document are good resources. According to these documents, ACAM2000 is approved for smallpox prevention and has limited, specific emergency use authorization for Mpox if JYNNEOS is unavailable. https://www.fda.gov/media/75792/download  

 

 

5) We must understand the history of smallpox vaccine. The first smallpox vaccine discovered by Edward Jenner in the 18th century was cowpox. But somehow the first vaccine used for mass vaccination was horsepox. Somehow, the horsepox was mysteriously replaced by vaccinia. We don't know where =vaccinia came form.  Do you have any information on the neurological effects of cowpox and horsepox in comparison to the modern day vaccinia?

Response: Thanks for the note

The following paragraph was added

The story of smallpox vaccine began in 1796 when Edward Jenner observed that milkmaids who had caught cowpox were immune to smallpox, inspiring him to test cowpox as a way to prevent smallpox. To test this idea, he inoculated a young boy with cowpox, successfully creating immunity to smallpox and developing the world’s first vaccine. By the 19th century, cowpox was replaced by horsepox in mass vaccinations due to supply challenges. However, around the 20th century, a virus called vaccinia became the standard in smallpox eradication efforts. When it comes to neurological side effects, cowpox and horsepox are thought to be milder, as they naturally occur less often in humans and typically cause minimal symptoms. Vaccinia, however, can lead to rare but serious neurological complications, including encephalitis, particularly in those with compromised immune systems [96-99].  

 

 

6) Line 531, "Most of the cases recover" should be changed " Most of the patients in those cases recovered.."

Response: Thanks for the note

Changed and Corrected

7) Line 532 "Some cases have.." should be replaced by "Some of the patients in those cases have.."

Response: Thanks for the note

Changed and Corrected

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Abstract:"

 

“JYNNEOS, which has fewer neurological risks”.

The reviewer has no knowledge of neurological risks, as this vaccine does not replicate as shown in numerous human studies including HIV patients and highly immune compromised mice. Hence, neurological risks are not expected. 

Author Response

 

Rev2:

JYNNEOS, which has fewer neurological risks”.

The reviewer has no knowledge of neurological risks, as this vaccine does not replicate as shown in numerous human studies including HIV patients and highly immune compromised mice. Hence, neurological risks are not expected.

Response: We are sorry for this unintended mistake.

Corrected.

Reviewer 3 Report

Comments and Suggestions for Authors

Don't quite understand line 129.  Did they mean

"Infectious types of intracellular viruses are formed BY late proteins". 

Next time the authors submit a new version of a manuscript, they should highlight the changes

Author Response

Response to reviewer 3 comments

 

Don't quite understand line 129.  Did they mean

"Infectious types of intracellular viruses are formed BY late proteins".

Response: We are sorry for this confusion.

We mean that "Late proteins are essential components for viral assembly and formation of infectious types of intracellular viruses"

We removed this confusion and replaced it by another clear one.  

 

Next time the authors submit a new version of a manuscript, they should highlight the changes

Response: Done